CN101115727A - Compounds useful for inhibiting chk1 - Google Patents
Compounds useful for inhibiting chk1 Download PDFInfo
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- CN101115727A CN101115727A CNA2005800353820A CN200580035382A CN101115727A CN 101115727 A CN101115727 A CN 101115727A CN A2005800353820 A CNA2005800353820 A CN A2005800353820A CN 200580035382 A CN200580035382 A CN 200580035382A CN 101115727 A CN101115727 A CN 101115727A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Aryl- and heteroaryl-substituted urea compounds useful in the treatment of diseases and conditions related to DNA damage or lesions in DNA replication are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating cancer and other diseases characterized by defects in DNA replication, chromosome segregation, or cell division also are disclosed.
Description
Invention field
The present invention relates to be used to suppress to keep and repair the compound of the enzyme of genetic material integrity.More particularly, the present invention relates to the carbamide compound that a series of aryl and heteroaryl replace, relate to the method for making these compounds and its as therapeutical agent treat cancer for example and be characterized as that thymus nucleic acid (DNA) duplicates, purposes in the other diseases of chromosome segregation or cell fission defective.
Background of invention
A large amount of diseases, illness and the patient's condition (hereinafter referred to as " indication ") are characterized as and relate to abnormal proliferation cell.Term used herein " abnormal proliferation cell " (or " abnormal cells hyperplasia ") meaning promptly departs from hyperplasia normal, suitable or the expection process.For example, the abnormal cells hyperplasia comprises unsuitable cell proliferation, wherein DNA or other cellular constituents sustain damage or defectiveness.The abnormal cells hyperplasia also comprises the indication that is caused or mediated or cause following situation by following situation: unsuitable high-level cell fission, unsuitable low-level necrocytosis (for example apoptosis) or the two have.For example, these indications are characterized as the single or multiple local anomaly propagation of cell, cell mass or tissue, comprise carcinous (optimum or pernicious) and non-carcinous indication.
With regard to definition, all cancers (optimum and pernicious) all relate to some abnormal cells hyperplasia form.Limiting examples comprises cancer and sarcoma.Being discussed below of other.Some non-carcinous indication also relates to the abnormal cells hyperplasia.The limiting examples that relates to the outgrowth non-carcinous indication of abnormal cells comprises rheumatic arthritis, psoriasis, vitiligo, Wegener granulomatosis and systemic lupus erythematous.Being discussed below of other.
A kind of method that treatment relates to the indication of abnormal proliferation cell relates to the agent of use dna damage.These damage agent are designed to by disturbing important cell processes (for example DNA metabolism, DNA synthesize, DNA transcribes and the microtubule spindle body forms) to kill and wound abnormal proliferation cell.For example, they also can work by damage being incorporated into the DNA that upsets the chromosome structure integrity.The dna damage agent designs in many ways and gives, and also makes necrocytosis subsequently to attempt inducing maximum to damage in abnormal proliferation cell, and normal healthy cell is produced minimum damage.
A large amount of dna damage agent had been developed so far already.Other also just under development.The dna damage agent comprises chemotherapeutics and radiation.Very unfortunate, the effectiveness that dna damage agent treatment relates to the outgrowth illness of abnormal cells always than institute's phase need low, especially aspect the treatment cancer.For healthy cell, this equivalent damage agent is qualified reluctantly usually at the selectivity (being sometimes referred to as therapeutic index) of abnormal proliferation cell.
In addition, all cells all has sensing mechanism and repair mechanism, and its processing to the dna damage agent may be conflicting.These sensing mechanisms are called the cell cycle check point, help to keep the order in each cellular replication stage, guarantee that each step carries out (Hartwell etc., Science, 246:629-634 (1989) with the high fidelity (Hi-Fi) degree; Weinert etc., Genes Dev., 8:652 (1994)).When cell detects dna damage, comprises by dna damage agent inductive when damage on purpose, some signal pathway activating cells cycle checkpoint, then cell replication cycle temporarily stops (" stagnation ").This stagnation makes abnormal proliferation cell repair its DNA if having time, and repairing usually is enough to make affected cell to continue the degree of survival and propagation.This undesired reparation is often disrupted furtively dna damage is induced to the effort that is enough to kill and wound abnormal proliferation cell.
For example, be called Gemzar
TM(gemcitabine or 2 ', 2 ' two fluoro-2 '-Deoxyribose cytidine) chemotherapeutics come damage dna among the DNA by between synthesis phase himself being incorporated at DNA.Usually become and to earn a bare living without the damage dna of repairing.Yet in a lot of target cells, this (or being what damage on the contrary) DNA that makes is irrelevantly detected in the cell cycle check point.The time that activated cell cycle check point trigger cell cycle arrest is enough to for one to make the DNA of damage to obtain repairing.This is the mode that a kind of wherein abnormal proliferation cell can be resisted the cell killing effect of dna damage agent (for example chemotherapeutics, radiation and other treatment) in theory.
Other dna damage agent cause that tumour cell is stuck in the S phase.Observed already when giving some chemotherapeutics, tumour cell is resisted these chemotherapeutics by being stuck in the S phase simply.So, in case remove medicine, DNA plerosis damage at once, cell cycle arrest stops, and cell is proceeded the remaining cell cycle (Shi etc., Cancer Res.61:1065-1072,2001).The other treatment agent causes that cell cycle arrest is in other check points that comprise G1 and G2 (elaboration in more detail below).This paper is called " check point activator " with the dna damage agent of activating cells cycle checkpoint usually.The dna damage agent that this paper is called activation the check point of " Chk1 " (pronouncing " check point-1 ") is called " Chk1 activator ".This paper briefly and particularly is called " check point inhibitor " and " Chk1 inhibitor " respectively with these check point inhibitor.
Therefore, expection suppresses each dna damage check point and helps to prevent cytothesis therapeutic inductive dna damage, and makes target cell to dna damage agent sensitivity.And then expect that these sensibilizeds improve the therapeutic index of these treatments.
In order to understand the present invention better, the effect of each phase of cell cycle and Chk1 is discussed in more detail below.
For all eucaryon species, the cell cycle its primary process with regulate pattern aspect be identical on 26S Proteasome Structure and Function.Mitotic division (somatocyte) cell cycle was made up of the fourth phase: G1 (gap) phase, S (synthesizing) phase, G2 (gap) phase and M (mitotic division) phase.G1, S and G2 phase are referred to as the interval of cell cycle.During the G1 phase, the biosynthesizing activity of cell is carried out at a high speed.When the synthetic beginning of DNA, the S phase begins; When nuclear DNA content had duplicated and form the identical karyomit(e) of 2 covers already, the S phase finished.
Cell enters the G2 phase then, and this phase lasts till that mitotic division begins.In mitotic division, chromosome pairing, separation form 2 new nucleus, division of cytoplasm occurs, and wherein cell fission is 2 daughter cells, and each obtains a nucleus that contains 1 cover in the 2 cover karyomit(e)s.Division of cytoplasm is through with the M phase, indicates that the interval of next cell cycle begins.The order that cell cycle events takes place is subjected to strict regulation and control, and the beginning of a cell cycle events like this is decided by finishing of front cell cycle events.This makes genetic material verily to duplicate from generation somatocyte to somatocyte of future generation and to separate.
Reported already that the cell cycle check point comprised the different polypeptide of at least 3 classes, its cell cycle signal or chromosomal mechanism defective are reacted and play a role successively (Carr, A.M., Science, 271:314-315 (1996)).The first kind is for surveying or sensation dna damage or unusual protein families of cell cycle.These detectors comprise ataxia-telangiectasis mutain (Atm) and ataxia-telangiectasis Rad associated protein (Atr).The signal that the second class polypeptide amplifies and conduction is surveyed by detector is an example with Rad53 (Alen etc., Genes Dev.8:2416-2488 (1994)) and Chk1.The 3rd class polypeptide comprises the cell cycle effector, p53 for example, its mediated cell reaction, for example mitotic division stagnation and apoptosis.
The understanding of current cell cycle check point function is mostly from the research to the clone in tumour source.Under many circumstances, tumour cell has been lost crucial cell cycle check point (Hartwell etc., Science 266:1821-28,1994).It is reported that the committed step that cell develops into the warty attitude is the sudden change that obtains to make cell cycle check point approach inactivation, for example relates to sudden change (Weinberg, R.A., the Cell 81:323 330,1995 of p53; Levine, A.J., Cell 88:3234 331,1997).Lose these cell cycle check points, although cause having the dna damage tumour cell still to duplicate.
Non-cancerous tissue with intact cell cycle checkpoint interrupts insulating because of single check point approach is temporary transient usually.Yet tumour cell has defective in the approach of control cell cycle progress, and the interference to other check point makes them responsive especially to the dna damage agent thus.For example, the tumour cell that contains the p53 mutant is in G1 dna damage check point with keep aspect the G2 dna damage check point ability two all defectiveness (Bunz etc., Science, 282:1497-1501,1998).The check point inhibitor that the expection target starts G2 check point or S phase check point can further weaken the ability that these tumour cell DNA plerosis are damaged, therefore, they are to improve the two the candidate (Gesner of therapeutic index of radiation and systemic chemotherapy, T., the SRIConference summary: Protein Phosphorylation and Drug Discovery WorldSummit, March 2003).
When existing as dna damage or to any obstruction of dna replication dna, check point albumin A tm and Atr initiating signal transduction pathway cause cell cycle arrest.Shown already that Atm worked in the dna damage check point that ionizing rays is replied.Atr is subjected to causing that the agent and the DNA radiating agent of blockading of double-stranded DNA fracture, single stranded DNA fracture stimulate.
Chk1 is protein kinase (Sanchez etc., Science, 277:1497-1501,1997 that are positioned at Atm and/or Atr downstream in dna damage checkpoint signals transduction pathway; United States Patent (USP) the 6th, 218, No. 109).In mammalian cell, Chk1 comprises that to causing the agent of dna damage (Sanchez etc. see above-mentioned for ionizing rays, ultraviolet (UV) line and hydroxyurea; Lui etc., Genes Dev., 14:1448-1459,2000) reply and by phosphorylation.The phosphorylation of the Chk1 of this activation mammalian cell depends on Atm (Chen etc., Oncogene, 18:249-256,1999) and Atr (Lui etc. see above-mentioned).In addition, shown already that Chk1 made weel (O ' Connell etc., EMBO J., 16:545-554,1997) and Pds1 (Sanchez etc., Science, 286:1166-1171,1999) both phosphorylations, the back both be known in cell cycle control important function of gene product very.
These studies have shown that, Mammals Chk1 works causing stagnating in the Atm of S phase dependent DNA damage inspection point.Effect (Feijoo etc., J.Cell.Biol., 154:913-923,2001 of Chk1 in S phase mammalian cell have been illustrated recently; Zhao etc., PNASUSA, 99:14795-800,2002; Xiao etc., J Biol Chem., 278 (24): 21767-21773,2003; Sorensen etc., Cancer Cell, 3 (3): 247-58,2003), emphasize the effect of Chk1 in the synthetic integrity of monitoring of DNA.Chk1 causes that by making the Cdc25A phosphorylation S phase stagnates, and (Xiao etc. see above-mentioned Cdc25A cell cycle regulation albumin A/cdk2 activity; With Sorensen etc., see above-mentioned).Chk1 is also by making the Cdc25C phosphorylation and making its inactivation cause that G2 stagnates, Cdc25C is a kind of dual specificity phosphatase enzyme, usually when proceeding to mitotic division, G2 makes cell periodic protein B/cdc2 (being also referred to as Cdk1) dephosphorylation (Fernery etc. when cell, Science, 277:1495-7,1997; Sanchez etc. see above-mentioned; Matsuoka etc., Science, 282:1893-1897,1998; With Blasina etc., Curr.Biol., 9:1-10,1999).In both cases, when having dna damage or during without the DNA that duplicates,, entering mitotic division to prevent cell to the active regulation and control inducing cell of Cdk cycle arrest.
The cell cycle check point inhibitor of other kinds plays a role at G1 or G2/M phase.UCN-01 or 7-hydroxyl Staurosporine are initial to be separated as the non-specific kinase inhibitor that mainly acts on protein kinase C, but has found that recently it can suppress the Chk1 activity and cancel G2 cell cycle check point (Shi etc. see above-mentioned).Therefore, UCN-01 is non-specific Chk1 inhibitor, and pair cell is poisonous when high dosage.When low dosage, it suppresses a lot of cell kinases non-specificly, also suppresses G1 check point (Tenzer and Pruschy, Curr.Med.Chem.Anti-Cancer Agents, 3:35-46,2003).
With UCN-01 and cancer therapy combined utilization, for example, obtained limited success already with radiation, anticarcinogen camptothecine (Tenzer and Pruschy see above-mentioned) and gemcitabine (Shi etc. see above-mentioned) associating.In addition, also UCN-01 is used for the spongioblast oncocyte and has strengthened the effect (Hirose etc., CancerRes., 61:5843-5849,2001) that Temozolomide (TMZ) inductive dna mismatch is repaired (MMR).Clinically, UCN-01 is not that as was expected is effective chemotherapeutic agent, may be owing to can not make treatment plan and can't differentiate concrete key molecule target (Grant and Roberts, Drug Resistance Updates, 6:15-26,2003).Therefore, reports such as Mack, UCN-01 cell cycle dependency ground in the non-small cell lung cancer cell system of cultivating strengthens the effect of cis-platinum, but do not identify the specificity (Mack etc. of the key cells cycle checkpoint of UCN-01 institute target, Cancer Chemother.Pharmacol., 51 (4): 337-348,2003).
Several strategies that make tumour cell to the treatment sensitivity of the chemotherapeutics that influences the cell cycle are arranged.For example, give 2-amino-purine and can cancel various kinds of cell cycle checkpoint mechanism, for example leucenol inductive G1 stagnates or the hydroxyurea inductive S phase stagnates, make cell continue to enter and by mitotic division (Andreassen etc., Proc Natl Acad Sci USA, 86:2272-2276,1992).Also be process and the inducing cell death (Bracey etc. thus that methyl xanthine is used for passing through by mediation the G2 check point with caffeine, Clin.Cancer Res., 3:1371-1381,1997), the cytotoxicity of enhancing dna damage agent (for example cis-platinum and ionizing rays).Yet, be used to realize that the caffeine dosage of cancelling the cell cycle surpasses acceptable level clinically, thereby can not select as spendable treatment.In addition, susceptibility (Yin etc., Biochem.Biophys.Res.Commun., 295:435-44 the kinase whose antisense nucleotide of Chk1 have been used to increase to topoisomerase enzyme inhibitor BNP1350,2002), but proof has the usually problem relevant with antisense therapy and gene therapy.
The Chk1 inhibitor also has been disclosed among WO 02/070494, WO 04/014876 and the WO03/101444.Additional C hk1 inhibitor comprises di-aryl urea compounds, for example: be disclosed in the carbamide compound that aryl among the U.S. Patent Publication No. 2003-0069284 A1 and heteroaryl replace; Methyl xanthine and relevant compound (Fan etc., Cancer Res., 55:1649-54 (1995); Urea groups thiophene (WO 03/029241); N-pyrrolopyridine methane amide (WO03/28724); Antisense Chk1 Nucleotide (WO 01/57206); Chk1 receptor antagonist (WO00/16781); Heterocyclic base carboxamide derivative (WO 03/037886); Aminothiophene (WO03/029242); (indazolyl) benzoglyoxaline (WO 03/004488); Heterocycle-oxyimino-fluorenes (WO 02/16326); The derivative (scytonemin) (United States Patent (USP) the 6th, 495, No. 586) that contains the scytoneman main chain; Heteroaryl benzamide (WO 01/53274); Indazole compound (WO01/53268); Indolocarbazole (, seeing above-mentioned) referring to Tenzer etc.; Chroman derivatives (WO 02/070515); Paullones (Schultz etc., J.Med.Chem., 42:2909-2919 (1999)); Indeno pyrazoles (WO 99/17769); Flavones (Sedlacek etc., Int.J.Oncol., 9:1143-1168 (1996); The peptide derivant (WO98/53050) of serine threonine kinases peptide ring; And oxindole (WO 03/051838).
Yet this area still needs effective and has optionally Chk1 inhibitor.The present invention endeavours to address this problem and satisfies other needs.
The invention summary
The present invention relates to the effective of check point kinase c hk1 and have optionally inhibitor.Chk1 inhibitor of the present invention is used for the treatment of and relates to the outgrowth indication of abnormal cells, and is used as chemotherapy sensitizing agent and radiation sensitizing agent in the treatment indication relevant with the infringement in dna damage or the dna replication dna.
Therefore, one aspect of the present invention provides structural formula (I) compound.These compounds are used to suppress the method for Chk1, and this method comprises and gives individual this step with the structural formula of significant quantity (I) compound.
Formula (I) compound has following structural formula:
X wherein
1For do not exist ,-O-,-S-,-CH
2-or-N (R
1)-;
X
2For-O-,-S-or-N (R
1)-;
Y is O or S; Or=Y represents 2 hydrogen atoms that are connected to shared carbon atom;
The C that W is selected from heteroaryl, aryl and is replaced by heteroaryl or aryl
1-6Alkyl, the wherein aryl of (a) described W or heteroaryl CF
3With at least one replacement in the heteroaryl; (b) the optional quilt of the aryl of described group W is by R
21-3 substituting group of representative replaces; (c) the optional quilt of the heteroaryl of described group W is by R
51-3 substituting group of representative replaces;
R
1Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and aryl;
R
2Be selected from heteroaryl, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, OCF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
3Be selected from hydrogen, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, aryl, heteroaryl, CO
2R
4, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group N (R
4)
2)
2, or 2 R
3The common 3-6 unit aliphatics ring that forms optional replacement of base;
R
4Be selected from hydrogen, C
1-6Alkyl, cycloalkyl, aryl, heteroaryl, C
1-6Alkylidene aryl and SO
2C
1-6Alkyl, or 2 R
4The common 3-6 unit ring that forms optional replacement of base;
R
5Be selected from C
1-6Alkyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
3)
2, OR
3, halogen, N
3, CN, C
1-6Alkylidene aryl, C
1-6Alkylidene group N (R
3)
2, C (O) R
3, C (O) OR
3, C (O) N (R
3)
2, N (R
1) C (O) R
3, N (R
1) C (O) OR
3, CF
3With
R
6Be selected from OR
11,-C ≡ C-R
7And heteroaryl;
R
7Be selected from hydrogen, C
1-6Alkyl, aryl, C
1-6Alkylidene aryl, heteroaryl, C
1-6Alkylidene group heteroaryl, alkoxyl group;
R
8, R
9And R
10Independently be selected from hydrogen, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OCF
3, CF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
8) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
11Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group N (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group-N (R
4)
2)
2
Or its drug acceptable salt or prodrug or solvate.
The present invention provides pharmaceutical composition and the purposes of said composition in the therapeutic treatment disease or the patient's condition that comprises one or more structural formulas (I) compound on the other hand, and wherein interior the or stripped Chk1 that suppresses of body provides the treatment benefit, or has research or diagnostic benefits.
Further aspect of the present invention provides the method for the cell sensitization that makes the individuality that just stands chemotherapy or radiotherapy in the treatment medical conditions, comprises structural formula (I) compound and chemotherapeutics, radiotherapeutic agents or these two united giving this individuality.Non-limiting indication by this method treatment is a cancer.
The present invention provides on the other hand and suppresses or the outgrowth method of prevention abnormal cells.In one embodiment, method comprises makes the cell mass that comprises abnormal proliferation cell contact with at least a Chk1 activator, is enough to the amount of activator and action time make the cell cycle arrest of abnormal proliferation cell synchronous basically.In case in cell mass, reach the cell cycle arrest basic synchronization, this cell mass is contacted with at least a Chk1 inhibitor, are enough to the amount of inhibitor and action time cancel basically this cell cycle arrest.
In the preferred embodiment that the present invention will describe in detail from below these and other aspects obviously as seen.
DESCRIPTION OF THE PREFERRED
The compounds of this invention has structural formula (I):
X wherein
1For do not exist ,-O-,-S-,-CH
2-or-N (R
1)-;
X
2For-O-,-S-or-N (R
1)-;
Y is O or S; Or=Y represents 2 hydrogen atoms that are connected to shared carbon atom;
The C that W is selected from heteroaryl, aryl and is replaced by heteroaryl or aryl
1-6Alkyl, wherein aryl of (a) described group W or heteroaryl are by CF
3With at least one replacement in the heteroaryl; (b) the optional quilt of the aryl of described group W is by R
21-3 substituting group of representative replaces; (c) the optional quilt of the heteroaryl of described group W is by R
51-3 substituting group of representative replaces;
R
1Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and aryl;
R
2Be selected from heteroaryl, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, OCF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
3Be selected from hydrogen, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, aryl, heteroaryl, CO
2R
4, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group N (R
4)
2)
2, or 2 R
3The common 3-6 unit aliphatics ring that forms optional replacement of base;
R
4Be selected from hydrogen, C
1-6Alkyl, cycloalkyl, aryl, heteroaryl, C
1-6Alkylidene aryl and SO
2C
1-6Alkyl, or 2 R
4The common 3-6 unit ring that forms optional replacement of base;
R
5Be selected from C
1-6Alkyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
3)
2, OR
3, halogen, N
3, CN, C
1-6Alkylidene aryl, C
1-6Alkylidene group N (R
3)
2, C (O) R
3, C (O) OR
3, C (O) N (R
3)
2, N (R
1) C (O) R
3, N (R
1) C (O) OR
3, CF
3With
R
6Be selected from OR
11,-C ≡ C-R
7And heteroaryl;
R
7Be selected from hydrogen, C
1-6Alkyl, aryl, C
1-6Alkylidene aryl, heteroaryl, C
1-6Alkylidene group heteroaryl, alkoxyl group;
R
8, R
9And R
10Independently be selected from hydrogen, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OCF
3, CF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
8) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
11Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group N (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group-N (R
4)
2)
2
With its drug acceptable salt or prodrug or solvate.
Preferred compound of the present invention is following compound, wherein X
1And X
2For-N (H)-;
Y is O or S; With
Preferred W is a heteroaryl.In one embodiment, W contains at least 2 heteroatomic heteroaryls that are selected from N, O and S, and described heteroaryl ring is optional to be selected from the optional C that replaces by one or two
1-6Alkyl, aryl, heteroaryl, N (R
3)
2, OR
3, C (O) N (R
3)
2, CO
2R
3, CN and halogen substituting group replace R wherein
3As defined above.
Other preferred structure formula (I) compounds are following compound, and wherein W is selected from pyridazinyl, pyrimidyl, pyrazinyl and triazinyl, and it is chosen wantonly and is selected from C by one or two
1-6Alkyl, aryl, heteroaryl, N (R
3)
2, C (O) N (R
3)
2, CO
2R
3, OR
3Replace with the substituting group of halogen.
In some preferred embodiment, W is selected from following structural:
With
It is optional by the individual C that is selected from of 1-4
1-6Alkyl, C
2-6Alkynyl, aryl, heteroaryl, CN, CO
2R
3, N (R
3)
2, OR
3Replace with the substituting group of halogen.
In more preferred, W is
In other preferred embodiments, heteroaryl substituting group and R on the W
6Heteroaryl independently be selected from
Term used herein " alkyl " comprises containing specifies carbonatoms purpose straight chain and branched hydrocarbyl, is generally methyl, ethyl and direct-connected and side chain propyl group and butyl.Unless otherwise noted, otherwise this alkyl can contain up to 20 carbon atoms.Term " alkyl " comprises " bridging alkyl ", i.e. C
6-C
16Two ring or multi-ring alkyls, for example norborneol alkyl, adamantyl, two ring [2.2.2] octyl groups, two ring [2.2.1] heptyl, two ring [3.2.1] octyl group or decahydro naphthyls.Alkyl is optional can be by for example hydroxyl (OH), halogen, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, amino (N (R
3)
2) and alkylsulfonyl (SO
2R
3) replacement, wherein R
3As defined above.
Term " cycloalkyl " is defined as ring-type C
3-8Alkyl, for example cyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl.Except this ring contained 1-3 heteroatoms that independently is selected from oxygen, nitrogen and sulphur, " Heterocyclylalkyl " definition was similar to cycloalkyl.Cycloalkyl and Heterocyclylalkyl can be to choose wantonly and independently are selected from C by 1-3
1-4Alkyl, C
1-3Alkylidene group OH, C (O) NH
2, NH
2, oxo (=O), the saturated or unsaturated loop systems of part that replaces of aryl, trifluoroacetyl group and OH.Heterocyclylalkyl can be chosen wantonly further by C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-3Alkylidene aryl or C
1-3The alkylidene group heteroaryl carries out N-and replaces.
Except containing carbon-to-carbon double bond, the definition of term " thiazolinyl " is with " alkyl ".
Except containing carbon-to-carbon triple bond, the definition of term " alkynyl " is with " alkyl ".
Term " alkylidene group " is meant and contains substituent alkyl.For example, term " C
1-6Alkylidene group C (O) OR " be meant the alkyl that contains 1-6 carbon atom that is replaced by-C (O) OR base.The optional substituting group of being done to choose wantonly to alkyl substituent by one or more fronts row of alkylidene group replaces.
This paper term " halogen " (" halo " or " halogen ") is defined as fluorine, bromine, chlorine and iodine.
This paper term " aryl " independent or associating is defined as monocycle or many cyclophanes perfume base, preferred monocycle or two cyclophane perfume base, for example phenyl or naphthyls.Unless otherwise noted, otherwise aryl can be unsubstituted, or for example independently is selected from following group replacement by one or more (especially 1-4): halogen, C
1-6Alkyl, C
2-6Thiazolinyl, OCF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
1) C (O) OR
3, N (R
1) C (O) C
1-3Alkylidene group C (O) R
3, N (R
1) C (O) C
1-3Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-3Alkylidene group OR
3, N (R
1) C (O) C
1-3Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-3Alkylidene group SO
2NR
3, C
1-3Alkylidene group OR
1And SR
3, R wherein
1And R
3As defined above.Exemplary aryl includes but not limited to phenyl, naphthyl, tetralyl, chloro-phenyl-, aminomethyl phenyl, p-methoxy-phenyl, trifluoromethyl, nitre phenyl base, 2,4-methoxychlor phenyl or the like.Term " aryl C
1-3Alkyl " and " heteroaryl C
1-3Alkyl " be defined as and contain C
1-3The aryl of alkyl substituent or heteroaryl.
Term " heteroaryl " is defined as monocycle or the bicyclic ring system that contains 1 or 2 aromatic nucleus and contain at least 1 nitrogen, oxygen or sulphur atom in aromatic nucleus.Unless otherwise noted, otherwise heteroaryl can be unsubstituted, or for example is selected from C by one or more (especially 1-4)
1-6Alkyl, aryl, heteroaryl, CF
3, CN, C (O) N (R
3)
2, CO
2R
2, N (R
3)
2, OR
3Replace with the substituting group of halogen, wherein R
3As defined above.The heteroaryl example includes but not limited to thienyl, furyl, pyridyl, azoles base, quinolyl, isoquinolyl, indyl, triazinyl, triazolyl, thiazolyl, different azoles base, imidazolyl (imidizolyl), benzothiazolyl, pyrazinyl, pyrimidyl, thiazolyl and thiadiazolyl group.
Term " hydrogen " is defined as-H.
Term " hydroxyl " is defined as-OH.
Term " nitro " is defined as-NO
2
Term " cyano group " is defined as-CN.
Term " isocyano-" is defined as-NC.
Term " trifluoromethoxy " is defined as-OCF
3
Term " azido-" is defined as-N
3
Term used herein " 3-8 unit ring " is meant carbocyclic ring and heterocycle aliphatic group or aromatic group, include but not limited to morpholinyl, pyridyl, phenyl, thienyl (thiophenyl), furyl, pyrryl, imidazolyl, pyrimidyl and pyridyl, optional exemplary group by aryl above one or more (especially 1-3) replaces.
Minimum and maximum number that the amount of carbon atom of hydrocarbonaceous part is demarcated by this part carbon atom below represent, for example " C
1-6Alkyl " be meant alkyl with 1-6 carbon atom, comprise 1 and 6 carbon atom.
In this paper structural formula, for not marking substituent key, this substituting group is a methyl, for example
When not pointing out that being connected to ring goes up the substituting group of carbon atom, should be appreciated that this carbon atom contains the hydrogen atom of proper number.In addition, for example when not pointing out to be connected to the substituting group of carbonyl or nitrogen-atoms, should be appreciated that this substituting group is a hydrogen, for example
For
R-N is R-NH
2
Abbreviation " Me " is a methyl.Abbreviation CO and C (O) are carbonyl (C=O).
Symbol N (R
x) (wherein x represents letter or number, for example R
a, R
b, R
3, R
4Or the like) be used to represent two R that are connected to shared nitrogen-atoms
xBase.When using this symbol, R
xBase can be identical or different, is selected from by R
xThe defined group of base.
" Chk1 inhibitor " meaning is known or the active any compound in the proteic cell cycle check point of the Chk1 of partial cancellation at least of later discovery, no matter it is natural existence or synthetic.When the checkpointing mechanism of defeating cell, when being enough to make cell certain phase by the cell cycle of original interruption to enter down first phase, or when making cell be directly to necrocytosis, just reached cancellation cell cycle check point.Cancellation cell cycle check point makes cell portability damage or defective enter each phase of cell cycle afterwards, induces thus or promotes necrocytosis.Necrocytosis can take place by any associative mechanism, comprises apoptosis and mitotic division disaster.
" Chk1 activator " meaning be known or later discovery can activate that DNA repairs and cell cycle check point stable state in the Chk1 kinase activity, it is induced to any agent of small part cell cycle arrest thus.The Chk1 activator comprises and can stagnate the agent of cell cycle in arbitrary phase of cell cycle that this paper can claim " the target phase " of this phase for this activator.The target phase comprises the phase of the arbitrary cell cycle except that m period, i.e. G1 phase, S phase and G2 phase.Be used for Chk1 activator of the present invention and comprise the dna damage agent, for example chemotherapeutics and/or radiation (or " radiotherapeutic agents "), for example ionizing rays or uv-radiation.The agent of Chk1 radioactivation includes but not limited to gamma-radiation, x-ray radiation, ultraviolet ray, visible light, ir radiation, microwave radiation and its mixing.
" inhibition abnormal cells hyperplasia " meaning promptly slows down or eliminates the speed that abnormal proliferation cell is bred.This inhibition can reduce from multiple-copy rate, cell mortality increases or these two.Necrocytosis can take place by any mechanism, comprises apoptosis and mitotic division disaster.
" prevention abnormal cells hyperplasia " meaning promptly suppressed the abnormal cells hyperplasia, or suppresses its recurrence before taking place.
" in the body " meaning is promptly in lived curee's body, as in animal or human's class body.Aspect this, the agent treatability is used for the curee to postpone or to eliminate the propagation of unusual replicating cell.These agents also can be used as prevention to be taken place or recurrence to prevent the abnormal cells hyperplasia, or prevents the symptom performance relevant with it.
The meaning that " exsomatizes " is promptly outside the lived curee that lives.Isolated cells group's example comprises vitro cell culture and from the biological sample of the mankind or animal, for example flow liquid sample or tissue sample.Can obtain these samples by the method that present technique is known.Exemplary biological liquids sample comprises blood, celiolymph, urine, saliva.Exemplary tissue sample comprises tumour and its slicer.Aspect this, aspect The compounds of this invention can and test two in treatment multiple application is arranged.
Term used herein " radiation sensitizing agent " is defined as with the treatment significant quantity and gives the mankind or other animals, to increase cell to the susceptibility of electromagnetic radiation and/or promote the compound of the treatment of diseases of available electromagnetic radiation treatment.
Term used herein " electromagnetic radiation " and " radiation " include but not limited to the radiation of 10-20 to 100 nano wave lengths.
The present invention includes all possible steric isomer of structural formula (I) compound and geometrical isomer.The present invention not only comprises racemic compound, and comprises optically active isomer.When expecting that structural formula (I) compound is single enantiomer, can obtain by splitting end product, or by synthetic from isomery pure starting material or use chiral auxiliary reagent stereotaxis, for example referring to Ma etc., Tetrahedron.:Asymmetry, 8 (6), 883-888 page or leaf (1997).Can finish end product, intermediate or starting material by any suitable method known in the art splits.In addition, have under the situation of structural formula (I) compound tautomer, this invention is intended to comprise all tautomeric forms of these compounds.Such as hereinafter proof, directed steric isomer and chemotherapy or radiotherapy associating can show the ability of unusual inhibition Chk1.
The prodrug of structural formula (I) compound also can be used as the compound in the inventive method.Definite fully, with compound deriving is to be suitable for preparing and/or prodrug approach that the form that gives discharges in vivo as medicine then, be successfully used to the physics-chem characteristic that temporary transient (biological example reversibly) change this compound (referring to H.Bundgaard editor " Design of Prodrugs; " Elsevier, Amsterdam, (1985); Silverman, " The Organic Chemistry of DrugDesign and Drug Action, " chapter 8 for Academic Press, San Diego, (1992); Hillgren etc., Med.Res.Rev., 15,83 (1995)).
The compounds of this invention can contain one or more functional groups.Need or in case of necessity, can modify this functional group so that prodrug to be provided.For example, suitable prodrug comprises acid derivative, for example acid amides and ester class.Those skilled in the art will appreciate that also the N-oxide compound can be used as prodrug.
Term used herein " drug acceptable salt " is meant and contains acidic moiety and form structural formula (I) compound with suitable cation salt.Positively charged ion be can accept on the suitable medicine and alkalimetal ion (for example sodium or potassium) and alkaline-earth metal (for example calcium or magnesium) positively charged ion comprised.In addition, contain basic center structural formula (I) compound drug acceptable salt for medicine on can accept the acid salt that acid forms.Limiting examples comprises hydrochloride, hydrobromate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, benzoate, succinate, fumarate, maleate, lactic acid salt, Citrate trianion, tartrate gluconate, mesylate, benzene sulfonate and tosilate.According to aforementioned, as long as mention the The compounds of this invention that this paper occurs, be intended to comprise structural formula (I) compound with and drug acceptable salt or solvate.
The compounds of this invention can be used as pure chemistry medicine therapeutic and gives, but also can be used as pharmaceutical composition or preparation gives structural formula (I) compound.Therefore, the invention provides pharmaceutical composition, it comprises on formula (I) compound and the medicine can accept diluent or carrier.The method of pharmaceutical compositions also is provided, comprises and mixing accepting diluent or carrier on formula (I) compound and the medicine.
Therefore, the present invention further provides pharmaceutical preparation, it comprises can accept carrier and optional other treatment component and/or prevention component on structural formula (I) compound or its drug acceptable salt, prodrug or solvate and one or more medicines.These carriers are being " can accept " with other component compatibility of said preparation and on to the nontoxic meaning of its recipient.For example, these carriers can be at Remington ' s Pharmaceutical Sciences, 17th Ed., and MackPublishing Co., Easton, PA. finds in (1985).
Usually measure with dose response and measure the kinase whose inhibition in check point, wherein allow responsive mensuration system contact with the purpose compound of finite concentration scope, described concentration range comprises does not see the concentration of finding the concentration of effect or observing minimum effect, via observing the partly higher concentration of effect, to the saturation concentration of observing maximum efficiency.In theory, these mensuration of the dose response effect of inhibitor compound can be described as sigmoid curve, and its expression is as the inhibition degree of concentration function.Also be enough to reduce the point of check point enzymic activity on this curve theory to 50% level of minimum of measuring and maximum enzyme activity difference by concentration.This concentration is defined as " inhibition concentration (50%) " or " IC
50" value.Available routine biochemistry (acellular) determination techniques or finish IC based on the determination techniques of cell
50The mensuration of value.
The comparison of inhibitor effect is usually with reference to contrast IC
50Value provides, wherein higher IC
50Show that this test compound is littler than the effect of reference compound thing, and low IC
50Show that this compound is bigger than the effect of reference compound thing.When measuring measurement with dose response, The compounds of this invention shows IC
50Value is low to moderate 0.1nM less than 5 μ M.Preferred compound shows the IC of 500nM
50Value or littler.More preferably The compounds of this invention shows IC
50Value is less than 250nM or littler, 100nM or littler, 50nM or littler, 20nM or littler.
Preferred Chk1 inhibitor of the present invention has selectivity, is promptly showing the selectivity that is at least 20 times of following protein kinases aspect the inhibition Chk1: protein kinase A, protein kinase C, cdc2 and pp60v-src.Preferred Chk1 inhibitor of the present invention is preferably showing the selectivity that is at least 75 times of following protein kinases aspect the inhibition Chk1: protein kinase A, protein kinase C, cdc2 and pp60v-src.Most preferred Chk1 inhibitor of the present invention shows 100 times the selectivity that is at least protein kinase A, protein kinase C, cdc2, pp60v-src, protein kinase B/Akt-1, p38MapK, ERK1, p70S6K, cdc2, cdk2, Chk2 and ab1 Tyrosylprotein kinase." times selectivity " is defined as the IC of the kinase whose Chk1 inhibitor that is used for comparison
50IC divided by the Chk1 inhibitor that acts on Chk1
50
Be applicable to that compound of the present invention and pharmaceutical composition comprise that the active ingredient that wherein gives significant quantity is to reach the compound and the pharmaceutical composition of its plan purpose.More particularly, " treatment significant quantity ", meaning promptly are enough to treat the amount of suffering from the individual of indication or alleviating the existing symptom of this indication.Measure the treatment significant quantity fully in those skilled in the art's limit of power, especially under according to detailed description situation provided herein.
Except the Chk1 inhibitor, pharmaceutical composition of the present invention can with comprise the allotment of cytokine, lymphokine, somatomedin, other Hemopoietic factors or its mixture, give separately to reduce that this pharmaceutical composition is produced or the adverse side effect relevant with it.The cytokine that in pharmaceutical composition of the present invention, is particularly useful, lymphokine, somatomedin or other Hemopoietic factors include but not limited to M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN, TNF, G-CSF, Meg-CSF, GM-CSF, thrombopoietin, STEM CELL FACTOR, erythropoietin, angiogenin (comprises Aug-1, Ang-2, Ang-4, Ang-Y and/or human angiogenin-like polypeptide), vascular endothelial growth factor (VEGF), angiogenine, Delicious peptide-1 (BMP-1), BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, bmp receptor IA, bmp receptor IB, Brain Derived Neurotrophic Factor, ciliary neurotrophic factor, the neutrophilic granulocyte chemokine 1 of cntf receptor cytokine induction, the neutrophilic granulocyte chemokine 2 of cytokine induction, the neutrophilic granulocyte chemokine 2 of cytokine induction, endothelial cell growth factor (ECGF), endothelin 1, Urogastron, the neutrophilic granulocyte attractive substance in epithelial cell source, fibroblast growth factor (FGF) 4, FGF5, FGF6, FGF7, FGF8, FGF8b, FGF8c, FGF9, FGF10, acid FGF, basic FGF, glial cellline-derived neurotrophic factor acceptor 1, glial cellline-derived neurotrophic factor acceptor 2, growth associated protein, growth associated protein, growth associated protein, growth associated protein, Heparin-binding EGF-like growth factor, pHGF, hepatocyte growth factor receptor, insulin-like growth factor I, IGF-1, insulin-like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukaemia inhibitory factor, the leukaemia inhibitory factor acceptor, nerve growth factor, trk C, neurotrophin-3, neurotrophin-4, placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor (ECGF), Thr6 PDGF BB, Thr6 PDGF BB A chain, Thr6 PDGF BB AA, Thr6 PDGF BB AB, Thr6 PDGF BB B chain, Thr6 PDGF BB BB, platelet derived growth factor receptor, platelet derived growth factor receptor, the pre-B cell growth stimulating factor, STEM CELL FACTOR, the STEM CELL FACTOR acceptor, transforming growth factor (TGF), TGF, TGF1, TGF 1.2, TGF2, TGF3, TGF5, potential TGF1, TGF, conjugated protein I, the conjugated protein II of TGF, the conjugated protein III of TGF, Tumor Necrosis Factor Receptors I type, Tumor Necrosis Factor Receptors II type, the urokinase type plasminogen activator acceptor, vascular endothelial growth factor and chimeric protein and its biology or its immunocompetence fragment.
Structural formula (I) compound also can be puted together or be connected with the auxiliary part of the beneficial property of this compound of promotion in the treatment application method.These conjugates can be promoted these compounds are delivered to particular anatomical site or purpose zone (for example tumour), make lasting treatment concentration compound is arranged in target cell, change the pharmacokinetics and the pharmacokinetics character of these compounds, and/or improve the therapeutic index or the security pattern of these compounds.For example, suitable slave part comprises amino acid, oligopeptides or polypeptide, for example antibody, for example monoclonal antibody and Other Engineering antibody; With target cell or organize the natural or artificial part of acceptor.Other suitable slave parts comprise the lipid acid that promotes this compound bio distribution and/or target cell to absorb this compound or lipid part (for example referring to Bradley etc., Clin.Cancer Res. (2001) 7:3229).
Preparation of the present invention can standard manner be used for the treatment of the disease of pointing out, for example by oral, parenteral, see through mucous membrane (for example hypogloeeis or give by buccal), part, transdermal, rectum or suction (for example nasal cavity or deep lung suction) and give.Parenteral include but not limited to in intravenously, intra-arterial, intraperitoneal, subcutaneous, intramuscular, the sheath and the intraarticular mode give.Parenteral gives also available pressure technique such as POWDERJECT
TMFinish.
For oral administration and buccal administration, composition can be tablet form or the lozenge form with the usual manner allotment.For example, the tablet and the capsule that are used for oral administration can contain conventional excipients, for example tackiness agent (for example syrup, Sudan Gum-arabic, gelatin, sorbyl alcohol, tragacanth gum, starch slurry or polyvinylpyrrolidone), weighting agent (for example lactose, sucrose, sugar, Microcrystalline Cellulose, W-Gum, calcium phosphate or sorbyl alcohol), lubricant (for example Magnesium Stearate, stearic acid, talcum powder, polyoxyethylene glycol or silica), disintegrating agent (for example yam starch or Vivastar P 5000) or wetting agent (for example sodium lauryl sulphate).Tablet can be according to present technique well-known process dressing.
Perhaps, for example, The compounds of this invention can join in the oral liquid (for example water-based or oiliness suspensoid, solution, emulsion, syrup or elixir).In addition, the preparation that contains these compounds can be rendered as dry products, is used for water or the reconstruction of other suitable solvents before use.These liquid preparations can contain conventional additives, for example suspension agent, for example sorbitol syrups, methylcellulose gum, glucose/syrup, gelatin, Natvosol, Vltra tears, carboxymethyl cellulose, aluminium stearate gel and hydrogenation edible-fat; Emulsifying agent, for example Yelkin TTS, the smooth monoleate of sorb or Sudan Gum-arabic; Non-aqueous solvent (can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, oily ester, propylene glycol and ethanol; And sanitas, for example methyl p-hydroxybenzoate or ethyl ester and Sorbic Acid.
These preparations also can be formulated as suppository, for example contain conventional suppository bases, for example theobroma oil or other glyceryl ester.The composition that is used to suck usually can solution, the form of suspensoid or milk sap provides, its can be used as dry powder or with conventional propellent for example the aerosol form of Refrigerant 12 or trichlorofluoromethane give.Typical part and preparation capable of permeating skin, for example eye drops, creme, paste, lotion and paste comprise conventional water-based or non-aqueous solvent or for being added with plaster, patch or the film form of medicine.
In addition, the present composition can be prepared and be used for giving by injection or continuous infusion parenteral.Can be the form of the suspensoid, solution or the milk sap that are stored in oiliness or aqueous vehicles in injection preparation, can contain blender, for example suspension agent, stablizer and/or dispersion agent.Perhaps, active ingredient can be used for rebuilding with suitable solvent (for example aseptic, apirogen water) before use by dry powder form.
Also the present composition can be formulated as sustained release preparation.Can be by implanting (for example subcutaneous or intramuscular) or giving these prolonged action preparations by intramuscular injection.Therefore, The compounds of this invention can be allocated with suitable polymeric material or hydrophobic material (for example being stored in the milk sap that can accept in the oil), ion exchange resin or microsolubility derivative (for example slightly soluble salt).
Use for the animal doctor, formula (I) compound or its drug acceptable salt, prodrug or solvate can be used as and put into practice the consistent suitable preparation accepted with the standard animal doctor and give.The animal doctor can be easy to determine to be suitable for most the dosage regimen and the route of administration of particular animals.The animal of available Compounds and methods for treatment of the present invention includes but not limited to pet, domestic animal, animal for display and zoological park sample.
Synthetic method
Can prepare The compounds of this invention by following synthesis flow.Starting material can obtain from commercial source, or prepare by the literature method of having established known to persons skilled in the art.Unless following dated in addition, otherwise X, R
1, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10And R
11Group as defined above.R
2As defined above, also comprise CF in the following synthesis flow
3And heteroaryl.
Flow process 1
Shown in flow process 1, can be by for example DIEA and diphenylphosphine acylazide are handled from formula 6 compound formulas 4 compounds with alkali.The typical solvent of this reaction is THF, carries out under room temperature 1-12 hour after being reflected at blast shield.
Flow process 2
The alternative of flow process 2 displaying formulas 5 compounds synthesizes.With formula 7 compound treatment formulas 3 compounds, formula 7 compounds prepare by flow process 3.Useful non-limiting solvent is DMF, and temperature of reaction remained between room temperature and 60 ℃ about 1-12 hour.
Flow process 3
Shown in flow process 3, can be for example in the presence of the pyridine, by handling, from formula 8 compound formulas 7 compounds with chloroformic acid aryl ester (for example phenyl chloroformate or p-nitrophenyl chloroformate ester) at alkali.The non-limiting solvent that is used for this reaction comprises CH
2Cl
2Or pyridine, temperature from 0 ℃ to room temperature.
Flow process 4
Flow process 4 is showed the method that obtains formula 3 compounds.For example in the presence of sodium bicarbonate, salt of wormwood or the potassiumphosphate,, formula 1 compound is converted into formula 2 compounds at alkaline aqueous solution by handling with aryl boric acid and palladium (0) source (for example four (triphenylphosphines) close palladium).The non-limiting examples of solvents that is used for this reaction comprises THF, two alkane or glycol dimethyl ethers.This reaction under temperature between 0 ℃ and 90 ℃ about 1-12 hour usually.For example, in the presence of palladium on carbon, carbon coating platinum or zinc, formula 2 compounds are converted into formula 3 compounds.The examples of solvents that is used for this reaction includes but not limited to methyl alcohol, ethanol or acetate.Perhaps, with catalyzer for example two three (Phenylphosphines) of dichloro close palladium or any other palladium (0) source, formula 1 compound can be used to make terminal alkynes 11 arylations.Reaction usually exists alkali for example to carry out under the differing temps between the room temperature to 90 ℃ during Trimethylamine 99.
In addition, can obtain from formula 9 compounds, wherein X is trifluoromethanesulfonic acid (being tf) formula 1 compound.Typical reagent comprises trifluoromethanesulfanhydride anhydride or N-phenyl triflimide.This reaction is usually carried out under the temperature between-10 ℃ and the room temperature.Non-limiting examples of solvents is a methylene dichloride.Non-limiting alkali example is triethylamine or diisopropylethylamine.
Flow process 5
Flow process 5 is illustrated the alternative synthetic of formula 5 compounds.According to program shown in the flow process 2, formula 3 compounds can be converted into formula 10 compounds.According to program shown in the flow process 4, formula 10 compounds can be converted into formula 5 compounds then.
Flow process 6
Shown in flow process 6, can then add R by handling with alkali (for example salt of wormwood, triethylamine or sodium hydroxide)
11X (wherein X is halogenide, methylsulfonic acid base or toluenesulphonic acids base) is converted into formula 12 compounds with formula 11 compounds.The examples of solvents that is used for this reaction comprises DMF, THF, CH
2Cl
2With its mixture.This is reflected under the temperature between 0 ℃ and 100 ℃ and carried out about 15 minutes to 12 hours.
Perhaps, can be with formula 11 compounds and formula R
11The X compound, wherein X is a hydroxyl, be stored in solvent for example triphenylphosphine and the diisopropyl azodiformate among the THF handle resulting mixture, obtain formula 12 compounds.
Can in the presence of catalyzer (for example platinum oxide thing, palladium on carbon or Raney nickel), use hydrogen treat formula 12 compounds, or in the presence of metallic zinc, use acid source (for example saturated aqueous ammonium chloride or aqueous hydrochloric acid) processing formula 12 compounds, obtain formula 13 compounds.The examples of solvents that is used for this reaction comprises methyl alcohol, ethanol, ethyl acetate or its mixture.This reaction was carried out 1-12 hour in room temperature or the temperature below the room temperature usually.
Can be by allowing formula 13 compounds and formula 4 compounds (as preparation as described in the flow process 1) chemical combination come preparation formula 15 compounds.The examples of solvents that is used for this reaction comprises toluene, benzene and dimethylbenzene.This is reflected under 60 ℃ of-100 ℃ of temperature and carried out 5-12 hour.
Flow process 7
Flow process 7 has been showed the alternative synthetic of formula 15 compounds.With formula 7 compound treatment formulas 3 compounds, formula 7 compounds are by flow process 3 preparations.Spendable a kind of solvent is DMF, and temperature of reaction remains between room temperature and 60 ℃, and the reaction times is 1-12 hour.
Flow process 8
Flow process 8 has been showed alternative synthetic method of formula 15 compounds.For example handle with alcohol in the presence of sodium hydride, two (TMS) potassium amide or the positive fourth lithium at alkali, formula 19 compounds can be converted into formula 12 compounds.The examples of solvents that is used for this reaction comprises THF or diethyl ether.This reaction under the temperature between-15 ℃ and the room temperature about 1-6 hour usually.By program shown in the flow process 6 formula 12 compounds are converted into formula 15 compounds.
Flow process 9 is showed the alternative synthetic of compound 21 and 23.Program synthetic compound 20, wherein R shown in available flow process 5 or the flow process 6
2=Br.At alkaline aqueous solution for example in the presence of sodium bicarbonate, salt of wormwood or the potassiumphosphate, with heteroaryl boric acid (HetB (OH)
2) and palladium (0) source (for example four (triphenylphosphines) close palladium) processing, compound 20 can be converted into compound 21.The non-limiting examples of solvents that is used for this reaction comprises THF, two alkane or glycol dimethyl ethers.This reaction under the temperature between 0 ℃ and 90 ℃ about 1-12 hour usually.Perhaps, available heteroaryl stannate (HetSn (Bu) for example
3) replacement heteroaryl boric acid.
For example, for example in the presence of triethylamine or the HunigShi alkali, handle, also compound 21 can be converted into 22 with zinc cyanide and palladium (0) source (for example four (triphenylphosphines) close palladium) at alkali.The non-limiting examples of solvents that is used for this reaction was DMF and DME, 80 ℃ of reactions 1-12 hour.Perhaps, can in the presence of Pd (0) source (for example four (triphenylphosphines) close palladium) He Tongyuan (for example cupric iodide), obtain compound 22 from compound 21 with potassium cyanide.This reaction was usually carried out about 30 minutes to 5 hours under the temperature between room temperature and 200 ℃.The non-limiting examples of solvents that is used for this reaction comprises DMF.
At last, for example in the presence of the triethylamine,, compound 22 can be converted into compound 23 at alkali with for example sodium azide.The non-limiting examples of solvents that is used for this reaction comprises DMF or oil of mirbane.This reaction is the about 1-5 of temperature hour between 80 ℃ and 100 ℃ usually.
Below provide structural formula (I) compound concrete limiting examples, it synthesizes according to the method described in the U.S. Patent Application Publication No. 2003-0069284 A1 (being hereby incorporated by reference) of pending trial that propose below and common implements.
Used being abbreviated as in described herein synthesizing: hour (h), water (H
2O), sal epsom (MgSO
4), hydrochloric acid (HCl), methyl-sulphoxide (DMSO), diisopropyl azodiformate (DIAD), methylene dichloride (CH
2Cl
2), chloroform (CHCl
3), methyl alcohol (MeOH), ammonium hydroxide (NH
4OH), deuterochloroform (CDCl
3), tetrahydrofuran (THF) (THF), N-Methyl pyrrolidone (NMP), acetate (AcOH), sodium hydroxide (NaOH), ethyl acetate (EtOAc), ethanol (EtOH), methyl-sulphoxide (DMSO), diethyl ether (Et
2O), yellow soda ash (Na
2CO
3), sodium bicarbonate (NaHCO
3), nitric acid (HNO
3), sodium-chlor (NaCl), sodium sulfate (Na
2SO
4), dimethyl formamide (DMF), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) and N, N-two different-propyl group ethamine (DIEA).
Intermediate 1:
5-methyl-pyrazine-2-carbonyl azide
At room temperature (31.7mL, (25g 181mmol) in the suspension, obtains brown solution 181mmol) to join the 5-methyl-pyrazine-2-formic acid of the stirring that is stored in 540mL THF with DIEA in nitrogen.Then at blast shield after dropwise added diphenylphosphine acid azide (39.2mL, 181mmol) solution be stored in 50mL THF in 1 hour.This reactant stirring is spent the night.Then at room temperature with this reactant rotary evaporation to small volume, at Et
2O (1L) and H
2Distribute between the O (1L).With 2 * 250mL Et
2O reextraction H
2The O layer is with the organism of 2 * 1L saturated sodium bicarbonate washing merging.Dry (MgSO
4) this organism, to filter, the simmer down to solid piece is used Et
2O grinds, and obtains product, is yellow solid (15g, 50%).Can be by the xg crude product be dissolved in 20 * mL Et
2Also use the 1-2xg decolorizing charcoal at the room temperature treatment several minutes among the O, separate obtaining purer compound.After filtering and concentrating, this material is indicated as homogeneous with TLC in EtOAc, is pure white.The rate of recovery is generally 65%.
Compound 1:
1-[2-(piperidines-3-ylmethoxy)-5-trifluoromethyl-phenyl]-3-(5-trifluoromethyl-pyrazine-2-yl)-urea hydrochloride
Step 1:3-[2-(4-nitro-phenyloxycarbonyl amino)-4-trifluoromethyl-phenoxymethyl]-piperidines-1-t-butyl formate.(57uL 0.71mmol) joins and is stored in 2mL CH with pyridine in 0 ℃ in nitrogen
2Cl
2Stirring 3-(2-amino-4-trifluoromethyl-phenoxymethyl)-piperidines-1-t-butyl formate (240mg, 0.64mmol) in the solution, then add to p-nitrophenyl chloroformate ester (130mg, 0.64mmol).At 0 ℃ after 1 hour, use CH
2Cl
2This reaction mixture is diluted to 30mL, uses 2 * 30mL 2N HCl washing then, with 1 * 30mL water washing, with the water washing of 1 * 30mL salt.Dry (MgSO
4) this organism, filter simmer down to canescence foam.
Step 2:3-{4-trifluoromethyl-2-[3-(5-trifluoromethyl-pyrazine-2-yl)-urea groups]-phenoxymethyl }-piperidines-1-t-butyl formate.With 3-[2-(4-nitro-phenyloxycarbonyl amino)-4-trifluoromethyl-phenoxymethyl]-piperidines-1-t-butyl formate (217mg, 0.4mmol) and 5-trifluoromethyl-pyrazine-2-base amine (66mg, 0.4mmol) (press United States Patent (USP) the 4th, 293, No. 552 method preparation) in the 5mL reaction flask, mixes, with 400uL NMP dilution, cover lid as solid, as the dark yellow solution stirring, immerse then in 85 ℃ of oil baths and stirred 6 hours.With this reaction mixture cool to room temperature, stirring is spent the night.Under 0.5mm pressure, remove NMP in 80 ℃ then by the Kugekohr distillation.Use CH
2Cl
2Brown residue is diluted to 30mL, uses 3 * 30mL 1M Na then
2CO
3Washing is to remove p-nitrophenol.Dry (MgSO
4) organism, filtering, the rough solid of simmer down to grinds with EtOAc, filters, and obtains the product that institute's phase needs, and is white solid.
Step 3: the 2N HCl that will be stored in two alkane (2mL) in room temperature joins 3-[2-(4-nitro-phenyloxycarbonyl the amino)-4-trifluoromethyl-phenoxymethyl that covers the stirring that is stored in 2mL two alkane in the flask]-piperidines-1-t-butyl formate (60mg, 0.11mmol) in the solution, this reaction mixture stirred spend the night.Concentrate resulting suspension by rotary evaporation and high vacuum, obtain yellow solid (57mg, 99%) corresponding to end product.
1H-NMR(400MHz，d
6-DMSO)δ：11.18(brs，1H)，9.91(s，1H)，9.13(s，1H)，8.79(s，1H)，8.62(brs，1H)，8.57(s，1H)，7.43(d，1H)，7.25(d，1H)，4.18(m，2H)，3.44(m，1H)，3.23(m，1H)，2.86(m，2H)，2.36(m，1H)，1.96(m，1H)，1.83(m，1H)，1.67(m，1H)，1.42(m，1H)。LRMS (apci, cation mode) m/e 464.3 (M+1).
Compound 2:
1-[5-methyl-2-(piperidines-3-ylmethoxy)-phenyl]-3-(5-trifluoromethyl-pyrazine-2-yl)-urea hydrochloride
Step 1: press step 2 program of compound 1, from 3-[4-methyl-2-(4-nitro-phenyloxycarbonyl amino)-phenoxymethyl]-piperidines-1-t-butyl formate (WO 02/070494) preparation 3-{4-methyl-2-[3-(5-trifluoromethyl-pyrazine-2-yl)-urea groups]-phenoxymethyl }-piperidines-1-t-butyl formate.Separate this product, be white solid.
Step 2: press step 3 program of compound 1, from 3-{4-methyl-2-[3-(5-trifluoromethyl-pyrazine-2-yl)-urea groups]-phenoxymethyl }-piperidines-1-t-butyl formate prepares compound 2.Separate this end product, be yellow solid (30mg, 99%).
1H-NMR(400MHz，d
6-DMSO)δ：10.86(s，1H)，9.61(s，1H)，9.05(s，1H)，8.77(s，1H)，8.58(br s，1H)，7.98(s，1H)，6.98(d，1H)，6.83(d，1H)，3.99(m，2H)，3.40(m，1H)，3.23(m，1H)，2.81(m，2H)，2.23(m，1H)，2.22(s，3H)，1.91(m，1H)，1.80(m，1H)，1.62(m，1H)，1.39(m，1H)。LRMS (apci, cation mode) m/e410.4 (M+1).
Compound 3:
1-[5-methyl-2-(1-methyl-piperidines-3-ylmethoxy)-phenyl]-3-(5-trifluoromethyl-pyrazine-2-yl)-urea
Press step 2 program of compound 1,, be white solid from [5-methyl-2-(1-methyl-piperidines-3-ylmethoxy)-phenyl]-carboxylamine 4-nitro-phenyl ester (WO 02/070494) preparation compound 3.
1H-NMR(400MHz，CDCl
3)δ：11.01(br s，1H)，8.87(brs，1H)，8.82(s，1H)，8.44(s，1H)，8.17(s，1H)，6.84(d，1H)，6.76(d，1H)，3.84(m，2H)，3.16(m，1H)，2.81(m，1H)，2.37(s，3H)，2.29(m，1H)，2.20(s，3H)，1.99(m，1H)，1.87-1.62(m，4H)，1.11(m，1H)。LRMS (apci, cation mode) m/e 424.3 (M+1).
The non-limiting compound of other the present invention is illustrated as follows.
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Methods of treatment
The compounds of this invention can be used to add the result of treatment of severe radiation and/or chemotherapeutics, these radiation and/or chemotherapeutics are used for the treatment of cancer and other relate to eukaryotic hyperplasia indication, comprise the indication in human and other animals.For example, The compounds of this invention can be used for strengthening usually with the metabolic antagonist tumor treatment of methotrexate or 5 FU 5 fluorouracil (5-FU) treatment for example.Generally speaking, The compounds of this invention suppresses the abnormal proliferation cell of carcinous and non-carcinous two kinds of situations.
Use The compounds of this invention can cause abnormal proliferation cell partially or completely to disappear, promptly these cells partially or completely disappear from cell mass.Therefore, for example, when abnormal proliferation cell is tumour cell, the inventive method can be used to the tumor growth rate that slows down, dwindle the tumour size or reduce its quantity, or induced tumor partially or completely disappear.
In all embodiments, the present invention can do not identify the abnormal cells hyperplasia or do not taking place the abnormal cells hyperplasia, respectively suspect or expection when the abnormal cells hyperplasia is arranged in vivo or exsomatize and use.In addition, the present invention also can be recurred to prevent or to suppress the abnormal cells hyperplasia in the outgrowth use Anywhere of the abnormal cells of having treated in the past.In these and related embodiment, " cell mass that comprises abnormal proliferation cell " is meant and wherein do not identify as yet or the abnormal cells hyperplasia taking place, but suspect respectively or expect that it has the outgrowth arbitrary cell mass of abnormal cells, and/or treated the abnormal cells hyperplasia in the past to prevent or to suppress arbitrary cell mass of abnormal cells hyperplasia recurrence.
A kind of method of the present invention comprises unites the Chk1 inhibitor compound of the present invention and the chemotherapeutics for the treatment of significant quantity, and this chemotherapeutics can be realized strand or double-stranded DNA fracture, maybe can stop dna replication dna or hyperplasia.Perhaps, the inventive method comprises and unites the Chk1 inhibitor compound at least a of the present invention for the treatment of significant quantity and comprise using to have the antibody therapy of trastuzumab for example that suppresses the cancer cell proliferation activity.Therefore, cancer (for example colorectal carcinoma, head and neck cancer, carcinoma of the pancreas, mammary cancer, cancer of the stomach, bladder cancer, carcinoma vulvae, leukemia, lymphoma, melanoma, renal cell carcinoma, ovarian cancer, brain tumor, osteosarcoma and lung cancer) is to responsive by uniting the enhancing treatment that gives Chk1 inhibitor of the present invention and chemotherapeutics or antibody.
Cancer comprises tumour or vegetation, and they are wherein uncontrolled and continuously histiocytic growths of cell proliferation.Some these be grown to optimum, but other be called as " pernicious " can cause organism death.Malignant tumour or " cancer " are different from optimum growth, because except that the cell proliferation that shows offensiveness, also can invade surrounding tissue and transfer.In addition, malignant tumor feature is to show the structure and the surrounding tissue of losing more cytodifferentiation (more " dedifferenting ") and being relative to each other.This character is called as " anaplasia.”
The medicable cancer of the present invention also comprises solid tumor, i.e. cancer and sarcoma.Cancer comprises and is derived from epithelial malignant tumour, its infiltration (promptly invading) surrounding tissue, and produce and shift.Gland cancer is the cancer that is derived from glandular tissue or forms the tissue of discernible glandular structure.The cancer of another kind of big class comprises sarcoma, and this is the tumour that its cell is imbedded fibrous material or material of the same race (for example embryo's reticular tissue).The present invention also can treat the cancer of marrow or lymph material system of the same race, comprises leukemia, lymphoma and does not exist with the real piece of tumour usually but be distributed in other cancers of vascular system or lymphoreticular system.
The Chk1 activity is for example relevant with various cancer forms in the following areas: adult and pediatric tumor are learned, the growth of solid tumor/malignant tumour, mucoid circle cell cancer, local late tumor, metastatic cancer, people soft tissue sarcoma (comprising the Ewing sarcoma), cancer metastasis (comprising that lymphatic shifts), squamous cell cancer (head and neck cancer especially, esophageal squamous cell carcinoma, oral carcinoma), the hemocyte malignant change (comprises multiple myeloma, leukemia (comprises acute lymphoblastic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia)), exudative lymphoma (based on the lymphoma of body cavity), thymic lymphoma lung cancer (comprises small cell carcinoma, cutaneous T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adrenocortical carcinoma, produce the tumour of ACTH, non-small cell carcinoma, mammary cancer, comprise small cell carcinoma and duct carcinoma), gastrointestinal cancer (comprises cancer of the stomach, colorectal carcinoma, colorectal carcinoma with knot rectum tumorigenesis relevant polyp), carcinoma of the pancreas, liver cancer, urinary system cancer (comprises bladder cancer, for example primary shallow bladder tumor, aggressive transitional cell carcinoma of bladder and flesh aggressive bladder cancer), prostate cancer, the female genital tract malignant tumour (comprises ovarian cancer, primary peritonaeum epithelioma, cervical cancer, carcinoma of endometrium, carcinoma of vagina, carcinoma vulvae, uterus carcinoma and ovarian follicle solid tumor), male genetic road malignant change (comprising carcinoma of testis and penile cancer), kidney (comprising renal cell carcinoma), the cancer of the brain (comprises inner brain tumor (intrisic brain tumor), neuroblastoma, the stellate cell brain tumor, neurospongioma and the metastatic cancer cell of attacking central nervous system), osteocarcinoma (comprising osteoma and osteosarcoma), skin carcinoma (comprises malignant melanoma, the tumour progression of human skin keratinocyte and squamous cell cancer), thyroid carcinoma, retinoblastoma, neuroblastoma, ascites, pernicious ascites pleural fluid, mesothelioma, the WilmsShi tumour, carcinoma of gallbladder, trophoblastic tumor, hemangiopericytoma and Kaposi sarcoma.Therefore, expection gives the effect that Chk1 inhibitor of the present invention can improve treatment plan.
The compounds of this invention also can be strengthened the effect of pharmacological agent inflammatory diseases.Can be rheumatoid arthritis, psoriasis, vitiligo, Wegener granulomatosis and systemic lupus erythematous (SLE) from the disease example that obtains an advantage with the compound combination therapy that is suitable for the inventive method.The treatment of sacroiliitis, Wegener granulomatosis and SLE is usually directed to use immunosuppressive therapy, for example ionizing rays, methotrexate and endoxan.These treatments are directly or indirectly inducing DNA damage usually.Make these cells more responsive to the active inhibition of Chk1 in the damaged immunocyte to the control of these standard cares.Usually with uv-radiation (UV) and psoralene combination therapy psoriasis and vitiligo.The lethal effect of UV and psoralene is induced in dna damage agent of the present invention, improves the therapeutic index of this treatment plan.Generally speaking, when the compound that is used for the inventive method is united with the immunosuppressive drug that uses at present, can strengthen control to the inflammatory diseases cell.
Except the cancer that discloses above, the present invention also can be used for treating in the method for non-carcinous proliferative cell.These illnesss include but not limited to atherosclerosis, restenosis, vasculitis, ephritis, retinopathy, ephrosis, proliferative skin disorders, psoriasis, cicatrization, actinic keratosis, Stevens-Johnson syndrome, rheumatoid arthritis (RA), system's outbreak type JCA (JCA), osteoporosis, systemic lupus erythematous, eye hyperplasia disease (comprises that epithelium migrates to butt, proliferative vitreous body retinopathy (PVR)), diabetic retinopathy (diabetic retropathy), Hemangio hyperplasia disease, ichthyosis or papilloma.
A kind of preferred method that gives Chk1 inhibitor of the present invention is set forth in Keegan etc., in the U.S. Provisional Application the 60/503rd, No. 925 (file an application on September 17th, 2003, its whole content is hereby incorporated by reference).Be used to suppress outgrowth these methods of abnormal cells and relate to the scheme that gives Chk1 activator (for example chemotherapeutics) and Chk1 inhibitor of the present invention.In the method, at least a Chk1 activator gave with dosage and the time that is enough to inducing cell cycle arrest basic synchronization in proliferative cell.In case reach the cell cycle basic synchronization, then give at least a Chk1 inhibitor to eliminate cell cycle arrest, inductive treatment cell death.This method can with the same usefulness of any Chk1 activator, can be applicable to treatment or prevent carcinous and non-carcinous abnormal cells hyperplasia.
The abnormal proliferation cell group is contacted with a kind of Chk1 inhibitor, or with surpass a kind of Chk1 inhibitor and contact.Surpass a kind of Chk1 inhibitor if use, then these Chk1 inhibitor can be given simultaneously or be given in the different time by doctor in charge or experimental technique personnel decision.
Also can allow the abnormal proliferation cell group contact with a kind of Chk1 activator, or with surpass a kind of Chk1 activator and contact.Surpass a kind of Chk1 activator if use, then these Chk1 activator can be given simultaneously or be given in the different time by doctor in charge or experimental technique personnel decision.
Chk1 inhibitor of the present invention can be used to study or improve isolated cells group's behavior.For example, The compounds of this invention can be exsomatized is used for determining best dosage regimen, and/or determines the Chk1 inhibitor is given specific adaptations disease, cell type, patient's dosage, and determines other parameters.The information of collecting from these are used can be used for experiment purpose, or is used for designing clinically the external treatment scheme.Other suitable application of exsomatizing of the present invention are apparent to those skilled in the art.
Chk1 inhibitor compound of the present invention also can make cell that radiation is become responsive.The disease of available electromagnetic radiation treatment comprises neoplastic disease, optimum and malignant tumour and cancer cells.
The electromagnetic radiation treatment that this paper does not enumerate also is covered by the present invention.The electromagnetic radiation that the preferred embodiment of the invention adopts has: gamma-radiation (10
-20-10
-13M), x-ray radiation (10
-12-10
-19M), ultraviolet ray (10nm-400nm), visible light (400nm-700nm), ir radiation (700nm-1.0mm) and microwave radiation (1mm-30cm).
At present a lot of modality of cancer treatment adopt for example X-ray activated radiation sensitizing agent of electromagnetic radiation.X ray activated radiation sensitizing agent example includes but not limited to following: metronidazole, Misonidazole, go first Misonidazole, Pimonidazole, etanidazole, Nimorazole, ametycin, RSU 1069, SR 4233, EO9, RB 6145, niacinamide, 5-bromouracil deoxyribose (BUdR), idoxuridine (IUdR), bromine Deoxyribose cytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cis-platinum and the treatment of above material to go up effective analogue and derivative.
The photodynamic therapy of cancer (PDT) adopts the radioactivation agent of visible light as sensitizing agent.Photodynamics radiation sensitizing agent example includes but not limited to following: hematoporphyrin derivative, PHOTOFRIN
, benzoporphyrin derivative, NPe6, etioporphyrin tin (SnET2), pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanine, Phthalocyanine Zinc and the treatment of above material go up effective analogue and derivative.
Except that the Chk1 inhibitor, the radiation sensitizing agent also can be united with one or more compounds for the treatment of significant quantity and given, these compounds include but not limited to, promote the radiation sensitizing agent to be incorporated into the compound of target cell, control therapeutical agent, nutritive substance and/or oxygen flow into the compound of target cell, at the chemotherapeutics that has or do not have other radiation or treatment cancer or his disease treatment are effectively worked to tumour during other compounds.Can be used for other therapeutical agent example with radiation sensitizing agent combination and include but not limited to 5 FU 5 fluorouracil (5-FU), folinic acid, oxygen, carbogen (carbogen), red corpuscle input, perfluoro-carbon (FLUOSOL for example
-DA), 2,3-DPG, BW12C, calcium channel blocker, pentoxifylline, anti-angiogenic compounds, hydralazine and L-BSO.
Spendable chemotherapeutics includes but not limited to alkylating agent, metabolic antagonist, hormone and its antagonist, radiation isotope, antibody and natural product and its combination.For example, inhibitor compound of the present invention can be united with following material and given: microbiotic, for example Dx and the similar thing of other anthracyclines; Mustargen, for example endoxan; Pyrimidine analogue, for example 5 FU 5 fluorouracil; Cis-platinum; Hydroxyurea; Safe plain and it is natural and synthesis of derivatives or the like.As another example, in mixed rumour (mammary cancer for example, wherein tumour comprises the cell that relies on gonad-stimulating hormone and do not rely on gonad-stimulating hormone) under the situation, described compound can be united with leuproside or goserelin (the LH-RH peptide analogs of synthetic) and given.Other antitumor schemes comprise inhibitor compound and other treatment form combined utilization, for example surgical operation or radiation, and this paper is also referred to as " auxiliary antitumor form ".Be used for other chemotherapeutics of the present invention and comprise hormone and its antagonist, radio isotope, antibody, natural product and its combination.The chemotherapeutics example that is used for the inventive method is listed following table in.
| Alkylating agent | Mustargen | Mustargen |
| Endoxan | Ifosfamide | Melphalan |
| Chlorambucil | Nitrosourea | Carmustine (BCNU) |
| Lomustine (CCNU) | Semustine (Semustine) | Ethyleneimine/methylmelamine |
| Tretamine (TEM) | The support thio-phosphamide | (plug is for group) |
| Altretamine | (HMM, altretamine) | Alkyl sulfonate esters |
| Busulfan | Triazine | Dacarbazine (DTIC) |
| Metabolic antagonist | Folacin | Methotrexate |
| Trimetrexate | Pyrimidine analogue | 5 FU 5 fluorouracil |
| Fluorodeoxyuridine | Gemcitabine | Cytosine arabinoside |
| (AraC, cytosine arabinoside) | 5-azacytidine | 2,2 '-gemcitabine |
| Purine analogue | The 6-mercaptopurine | The 6-Tioguanine |
| Azathioprine | 2 '-deoxycoformycin | (pentostatin) |
| erythrohydroxynonyladenine | Fludarabine phosphate | 2-chlorodeoxyadenosine |
| (EHNA) | ||
| (CldAdo, 2-CdA) | Many targets antifolic | I type topoisomerase enzyme inhibitor |
| Camptothecine | Hycamtin | Irinotecan |
| Natural product | Anti-mitosis medicine | Taxol |
| Vinca | Vinealeucoblastine(VLB) (VLB) | Vincristine(VCR) |
| Vinorelbine | Taxotere (docetaxel) | Estramustine |
| Phosphoric acid estramustine epipodophyllotoxin | Etoposide | Teniposide |
| Microbiotic | Dactinomycin | Daunomycin (Rubomycin C) |
| Dx (Zorubicin) | The mitoxantrone idarubicin | Bleomycin Plicamycin (bleomycinsplicamycin) (Plicamycin) |
| Ametycin | Gengshengmeisu | Enzyme |
| The altheine enzyme | Biological response modifier | Interferon-' alpha ' |
| IL-2 | G-CSF | GM-CSF |
| Differentiation agent | Retinoic acid derivatives | The radiation sensitizing agent |
| Metronidazole | Misonidazole | Go the first Misonidazole |
| Pimonidazole | Etanidazole | Nimorazole |
| RSU 1069 | EO9 | RB 6145 |
| SR4233 | Niacinamide | 5-bromine uracil deoxyriboside |
| 5-iodine uracil deoxyriboside | The bromine cytosine deoxyriboside | Other class medicaments |
| Platinum coordination complex | Cis-platinum | Carboplatin |
| Oxaliplatin | Amerantrone | Mitoxantrone |
| Replace urea | Hydroxyurea | The methyl hydrazine derivative |
| N-methyl hydrazine (MIH) | Procarbazine | The adrenal cortex inhibitor |
| Mitotane (o, p '-DDD) | ainoglutethimide | Cytokine |
| Interferon, rabbit (α, β, γ) | Interleukin-2 hormone and antagonist | Adrenocortical steroid/antagonist |
| Prednisone and equivalent | Dexamethasone | ainoglutethimide |
| Progesterone | Hydroxyprogesterone caproate bp 98 | Medroxyprogesterone acetate |
| Magace | Oestrogenic hormon | Stilboestrol |
| Ethinylestradiol/equivalent | Estrogen antagonist | Tamoxifen |
| Male sex hormone | Testosterone propionate | Fluoxymesterone/equivalent |
| The resistance hormone | Flutamide | Gonadoliberin |
| Hormone analogs | Leuproside | The on-steroidal antiandrogen |
| Flutamide | Photosensitizers | Hematoporphyrin derivative |
| Photofrin | Benzoporphyrin derivative | Npe6 |
| Etioporphyrin tin (SnET2) | pheoboride-a | Bacteriochlorophyll-a |
| naphthalocyanines | Phthalocyanine | Phthalocyanine Zinc |
| Growth factor receptor antagonist | The EGFR antagonist | The HER-2 antagonist |
Especially can be used for comprising for example camptothecine with the chemotherapeutics example of radiation sensitizing agent associating, carboplatin, cis-platinum, daunorubicin, Dx, Interferon, rabbit (α, β, γ), irinotecan, hydroxyurea, Chlorambucil, 5 FU 5 fluorouracil (5-FU), methotrexate, 2-chlorine adenosine, fludarabine, azacytidine, gemcitabine, pemetrexed, interleukin-2, irinotecan, docetaxel, taxol, effective analogue and derivative are gone up in Hycamtin and the treatment of above material.
According to the present invention, The compounds of this invention can be used for and the gemcitabine associating, or unites with gemcitabine and taxol.The compounds of this invention also can be used for and the pemetrexed associating, or unites with pemetrexed and cis-platinum, carboplatin or other platinum classes.Chk1 inhibitor of the present invention also can be united with gemcitabine and pemetrexed and given.
Unite the Chk1 inhibitor of the present invention that gives with gemcitabine, can be used for treating for example carcinoma of the pancreas, leiomyosarcoma of uterus, osteosarcoma, transitivity nonsmall-cell lung cancer, four limbs and soft tissues of trunk's sarcoma, renal cell carcinoma, gland cancer and Hodgkin's disease.Can be used for treating mesothelioma with uniting the Chk1 inhibitor of the present invention that gives with pemetrexed.
Extend to prevention when as understood by the skilled person, this paper mentions treatment and treat fixed disease or syndromes.Mention the recurrence that treatment the time also refers to reduce hyperplasia speed or reduces the indication of having treated.Should be further appreciated that the amount that is used for the treatment of needed The compounds of this invention, change that it is finally by doctor in charge or animal doctor's decision with the characteristic of illness to be treated and patient's age and illness.
Yet, generally speaking, the dosage that adult treatment is used usually every day 0.001mg/kg in about 100mg/kg scope.Can single dose or give the amount that institute's phase needs easily with the suitable interval multiple doses, for example, give every day 2 times, 3 times, 4 times or more sub-doses.Decide the actual dosage regimen that is suitable for individual patient most by the doctor in the practice, this dosage is determined with age, body weight and the reaction of particular patient.Above-mentioned dosage is the exemplary dosage of general case, but individual cases can exist and should give higher or than low dosage, these all within the scope of the present invention.
Can contact these cell masses with the time to be enough to reaching basic any dosage of cancelling the cell cycle check point with Chk1 inhibitor of the present invention.Though unnecessary usually this equal time comprise and reach about 72 by about 96 hours that it is decided on various factors.In certain embodiments, determine that reaching several approximately weeks or giving the Chk1 inhibitor for more time is ideal or necessity as doctor in charge or technician.Therefore, Chk1 inhibitor of the present invention can give usually the following time: reach about 1 hour, reach about 2 hours, reach about 3 hours, reach about 4 hours, reach about 6 hours, reach about 12 hours, reach about 18 hours, reach about 24 hours, reach about 48 hours, or reach about 72 hours.Those skilled in the art understand, and time range shown in this paper only is exemplary, shown in these with interior or in addition scope or subrange also within the scope of the present invention.
Can give Chk1 inhibitor of the present invention by multiple dosage.For example, can give Chk1 inhibitor with lower frequency: every day 1 dosage was divided at interval with 4 days and send (q4dx4) 4 times; Every day 1 dosage was divided at interval with 3 days and to send (q3dx4) 4 times; To send at interval 1 dosage (qdx5) in 5 days every day; Send 1 dosage (qwk3) between 3 weeks weekly; Administration every day in 5 day was had a rest, again administration every day 5 days (5/2/5) in addition in 2 days; Or fixed any other dosage regimen that situation is fit to.
Embodiment
Embodiment 1
Measure the IC of Chk1 inhibitor
50Value
Announce WO No. 99/11795 and differentiate and clone people described in (on September 4th, 1998 filed an application) Chk1 cDNA as previous international application.The frame of FLAG mark according to the amino latter end of total length Chk1 inserted.5 ' primer contains EcoRI site, Kozak sequence, and also coding is used for M2 antibody (Sigma, Saint Louis, IL) the FLAG mark of affinity purification.3 ' primer contains the SalI site.With the fragment of pcr amplification as the EcoRI-SalI fragment cloning to pCI-Neo (Invitrogen, Carlsbad, CA), then with EcoRI-NotI fragment subclone to pFastBacI (Gibco-BRL, Bethesda, MD).As preparation recombinant baculovirus as described in the Gibco-BRL Bac-to-Bac handbook, be used for infecting being grown in the CCM3 substratum (UT) the Sf-9 cell in is to express the Chk1 albumen of FLAG -mark for HyClone Laboratories, Logan.
The Chk1 of purifying FLAG -mark from the freezing precipitation of the SF9 cell of baculovirus infection.(contain 100mM Tris-HCl pH 7.5,200mM NaCl, 50mM B-Phosphoric acid glycerol esters, 25mM NaF, 4mM MgCl with isopyknic 2X lysis buffer
2, 0.5mMEGTA, 0.2%TWEEN -20,2mM vanadic acid sodium, 2mM DTT) and the cell precipitation of protease inhibitor cocktail (Complete mini, Boehringer Mannheim 2000 catalog#1836170) mixed freezing.The loose pestle of using Dounce homogenizer then is cell homogenates 20 times, with 48, and centrifugal 1 hour of 400xg.50mM glycine pH 3.5 with 10 column volumes then uses 20mM Tris pH 7.5,150mM NaCl pre-wash M2 affinity matrix, alternately washes 3 times, finishes washing with Tris NaCl.Use 20mM Tris pH 7.5,150mM NaCl, 0.1%TWEEN -20,1mM EGTA, 1mM EDTA and the 1X complete mini protease tablet (proteolytic enzyme tablet) of 25 column volumes to wash this post then.Allow limpid lysate be attached to the M2 affinity resin at 4 ℃ then through 4 hours in batches.Then the mixture of resin and lysate is poured in the post, collected circulation liquid.20mM Tris pH 7.5,150mM NaCl and 3mM N-octyl glucoside washing resin with 10 column volumes.Then with the cold 20mM Tris pH 7.5, the 150mM NaCl that contain 0.5mg/mL FLAG peptide (Sigma, 2000 Catalog#F-3290) of 6 column volumes, 3mM N-octyl glucoside Chk1 from this post wash-out FLAG -mark.Collect 3 flow points, analyze the FLAG-mark Chk1 have a situation.
Protein kinase is used for the Chk1 kinase activity measures, this mensuration comprises FLAG -Chk1 (ATP/ of 150pmol minute), 20 μ m Cdc25C peptides (H-leu-tyr-arg-ser-pro-ser-met-pro-glu-asn-leu-asn-arg-ar g-arg-arg-OH) (SEQ ID NO:1), 4 μ m ATP, the 2 μ Ci[of 100ng purifying
32P] γ-ATP, 20mM Hepes pH 7.2,5mM MgCl
2, 0.1%NP40 and 1mM DTT.This mensuration is used to measure the IC of The compounds of this invention
50The reaction mixture that contains ATP by adding starts reaction, at room temperature carries out 10 minutes.Come termination reaction by adding phosphoric acid (150mM final concentration), and transfer to the phosphorylated cotton disk.With these phosphorylated cotton disks of 150mM phosphoric acid washing 5 times, air-dry.Add scintillation solution, count these disks with the Wallac scintillometer.The IC of the Chk1 inhibitor of being measured of the present invention
50Value is measured as about 8 to about 500nM.
Embodiment 2
Selectivity
Test the selectivity of Chk1 inhibitor of the present invention, promptly at the selectivity of DNA-PK, Cdc2, casein kinase i (CKI), Chk2, p38 map kinase, ERK kinases, protein kinase A (PKA) and/or calcium-calmodulin protein kinase ii (CaM KII) to one or more other protein kinases.Except that Chk2, all these kinase whose mensuration programs are described in following document in the past, comprise U.S. Patent Publication 2002-016521 A1 number and No. the 08/184th, 605, U.S. Patent application (filing an application on January 21st, 1994), these two all is hereby incorporated by reference.
Described compound is at the active following mensuration of Chk2: at 4mM ATP, 1mCi[
32P] γ-ATP, 20mM Hepes pH 7.5,5mM MgCl
2Exist with 0.25%NP40, in room temperature, allow down the 128ng purifying the His-mark Chk2 with up to the Chk1 inhibitor incubation of 100mM 20 minutes.With final concentration is the phosphoric acid termination reaction of 150mM, and 5/8 of reaction mixture is transferred to the phosphorylated cotton disk.With these disks of 150mM phosphoric acid washing 5 times, air-dry.Add scintillator, with Wallac β calculating instrument counting radioactivity.
P38 map kinase, ERK kinases, PKA, CaM KII and Cdc2 press manufacturer specification and implement to measure with 4-50 μ M ATP available from NewEngland Biolabs, and the Chk1 inhibitor concentration of test is up to 100 μ M.It is at least 100 times of other enzymes that all inhibitor of being surveyed all show selectivity to Chk1.
Embodiment 3
Chk1 inhibitor of the present invention suppresses the function of Chk1 in cell
For determining that Chk1 inhibitor of the present invention suppresses the function of Chk1 in cell, inhibitor can be tested in the molecular assay based on cell.Because proved Mammals Chk1 already in the external Cdc25C of making phosphorylation, show that it is replying and negative regulation cell periodic protein B/cdc2 dna damage, improve the active ability of cell periodic protein B/cdc2 so can analyze the Chk1 inhibitor.This experiment can design as follows: with the rayed HeLa cell of 800 rads, hatched 7 hours at 37 ℃.Because be the p53 feminine gender on these cell functions, they are exclusively stagnated in the G2 phase.Then, add the R 17934 of 0.5 μ g/mL concentration, allow cell hatch 15 hours at 37 ℃.Add R 17934 to catch any cell of stagnating M by G2.At last the Chk1 inhibitor was added 8 hours, harvested cell, cracking is according to proposal cell periodic protein B 1 antibody (New England Biolabs) the immunoprecipitation equal protein matter of manufacturers.Analyze the cdc2 kinase activity relevant (Yu etc., J Biol Chem., Dec.11,1998 in the immunoprecipitate by measuring the histone h1 kinase activity then with cell periodic protein B; 273 (50): 33455-64).
In addition, the ability of the G2 dna damage check point of described Chk1 inhibitor cancellation ionization radiation induction, available mitotic index determination experiment is determined.Handle HeLa cell (about 1 * 10 as mentioned above
6).By centrifugal cell harvesting, with the PBS washing once, be resuspended among the 75mM KCl of 2.5mL recentrifuge then.Then with the cold acetate of cell in the 3mL prepared fresh: fixing in the methyl alcohol (1: 3), hatched 20 minutes on ice.Sedimentation cell, the sucking-off stationary liquid is resuspended in cell among the 0.5mL PBS.Also covering sample with the 1mL stationary liquid prepares the mitotic division smear to microslide by pipetting 100 μ L fixed cells.Air-dry then slide with Wright Albert'stain Albert liquid (Sigma) dyeing 1 minute, then washes with water once, with 50% methanol wash once.There is condensation and lacks nuclear membrane and then be defined as mitotic cell.
Embodiment 4
Chk1 inhibitor of the present invention improves the ability by the cancer therapy killer cell
For proving that The compounds of this invention makes target cell become responsive more to the lethal effect of dna damage agent to the inhibition of Chk1, can hatch these cells, and contact with radiation or chemical dna damage agent in the presence of Chk1 inhibitor of the present invention.Cell contains 5%CO with the individual density bed board in 96 hole droplet plates of every hole 1000-2000 in 37 ℃ of humidities
2Incubator in the RMPI 1640 that contains 10%FBS, 100 U/mL penicillin and 100 μ g/mL Streptomycin sulphates the growth 18 hours.Institute's test cell can comprise any purpose cell or clone, for example HeLa, ACHN, 786-0, HCT116, SW620, HT29, Colo205, SK-MEL-5, SK-MEL-28, A549, H322, OVCAR-3, SK-OV-3, MDA-MB-231, MCF-7, PC-3, HL-60, K562 and MOLT4.All cells is that designate is meant following human cell system:
| HeLa | Adenocarcinoma of the uterine cervix |
| ACHN | Renal adenocarcinoma |
| 786-0 | Renal adenocarcinoma |
| HCT116 | Colorectal carcinoma |
| SW620 | Colorectal carcinoma, nodus lymphoideus transferring rate |
| HT-29 | Colon intestines rectal adenocarcinoma |
| Colo205 | Adenocarcinoma of colon |
| SK-MEL-5 | Melanoma |
| SK-MEL-28 | Malignant melanoma |
| A549 | Lung cancer |
| H322 | Bronchioalveolar carcinoma |
| OVCAR-3 | Adenocarcinoma ovaries |
| SK-OV-3 | Adenocarcinoma ovaries |
| MDA-MB-231 | Mammary cancer |
| MCF-7 | Mammary cancer |
| PC-3 | From the prostate cancer of transferring to bone |
| HL-60 | Acute promyelocytic leukemia |
| K562 | Chronic lymphocytic leukemia |
| MOLT4 | Acute lymphoblastic leukemia; The T lymphocytoblast |
With singly containing chemotherapeutic or containing chemotherapeutic and the substratum of Chk1 inhibitor processing cell.Passing through mensuration
3H-thymidine absorption level is measured before the growth, and cell was hatched about 5 days.Chemotherapeutic comprises Etoposide, Dx, cis-platinum, Chlorambucil, 5 FU 5 fluorouracil (5-FU).The cell growth-inhibiting is defined as GI to 90% of untreatment control cell required drug level
90
Available other metabolic antagonist comprises methotrexate, hydroxyurea, 2-chlorine adenosine, fludarabine, azacytidine and gemcitabine, tests The compounds of this invention, to assess the ability that described compound strengthens above-mentioned metabolic antagonist lethal effect.Can unite enhancing to the HT29 colorectal carcinoma lethal effect The compounds of this invention that is compared to each other by assessment and gemcitabine.
In addition, can measure the ability of Chk1 inhibitor enhanced rad lethal effect of the present invention.
Embodiment 5
Animal tumor model
For advance copy invention Chk1 inhibitor strengthens the ability of the tumour that the dna damage agent kills and wounds in mouse, be to set up the xenotransplantation tumor model with colon tumor cell.5 FU 5 fluorouracil (5-FU) or gemcitabine can be used as the dna damage agent.Available HT29 and Colo205 (human colon's cancer) and H460 and Calu-6 (non-small cell carcinoma) cell be breeding xenotransplantation tumour in 6-8 female thymus gland Balb/c (nu/nu) mouse in age in week.Mouse is raised in the laminar flow cupboard of anosis old terms, arbitrarily aseptic food of feeding and water.Allow clone in RPMI 1640 substratum that are supplemented with 10%FBS, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates and 1.5mM L-glutaminate in 5%CO
2Wet environment in grow into inferior the fusion.Prepare single-cell suspension liquid with CMF-PBS, cell concn is adjusted into 1 * 10
8Cell/mL.At right side of mice belly or right leg subcutaneous (s.c.) inoculation total amount is 1 * 10
7Cell (100 μ L).
Mouse is divided at random (5-15 mouse/group) 4 treatment groups, when tumour reaches 75-100cm3 volume (usually after inoculation 7-11 days), uses.Use the vernier caliper measurement tumour, estimate gross tumor volume with being derived from empirical formula: gross tumor volume (cm
3)=length of tumor (cm) * tumour width (cm) * tumor thickness (cm)/3.3.Treatment is made up of the 160mg/kg gemcitabine of intraperitoneal (i.p) injection 100 μ L.In mouse, observe the tumor growth sluggishness with the gemcitabine treatment.With 160mg/kg gemcitabine and the two combination therapy mouse of orally give Chk1 inhibitor, expection can be dwindled gross tumor volume and prolong life.Every other day monitor the tumour size one time at experimental session.
Obviously, can as indicated abovely carry out much not departing from the correction and the change of its spirit and scope to the present invention, therefore pointed as accessory claim, only these restrictions should be included.
Sequence table
<110>ICOS Corporation
＜120〉be used to suppress the compound of CHK1
<130>27866/40321A
<150>US 60/602,968
<151>2004-08-19
<160>1
<170>PatentIn version 3.3
<210>1
<211>16
<212>PRT
＜213〉artificial sequence
<220>
＜223〉synthetic peptide
<400>1
Leu Tyr Arg Ser Pro Ser Met Pro Glu Asn Leu Asn Arg Arg Arg Arg
1 5 10 15
Claims (28)
1. the compound with following formula and its drug acceptable salt or prodrug or solvate:
X wherein
1For do not exist ,-O-,-S-,-CH
2-or-N (R
1)-;
X
2For-O-,-S-or-N (R
1)-;
Y is O or S; Or=Y represents 2 hydrogen atoms that are connected to shared carbon atom;
The C that W is selected from heteroaryl, aryl, Heterocyclylalkyl, cycloalkyl and is replaced by heteroaryl or aryl
1-6Alkyl, wherein aryl of (a) described W group or heteroaryl are by CF
3With at least one replacement in the heteroaryl; (b) aryl of described W group is optional individual by R by 1-3
2The substituting group of representative replaces; (c) heteroaryl of described W group is optional individual by R by 1-3
5The substituting group of representative replaces;
R
1Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and aryl;
R
2Be selected from heteroaryl, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, OCF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
3Be selected from hydrogen, halogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, aryl, heteroaryl, CO
2R
4, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group N (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group N (R
4)
2)
2, or 2 R
3The common 3-6 unit aliphatics ring that forms optional replacement of base;
R
4Be selected from hydrogen, C
1-6Alkyl, cycloalkyl, aryl, heteroaryl, C
1-6Alkylidene aryl and SO
2C
1-6Alkyl, or 2 R
4The common 3-6 unit ring that forms optional replacement of base;
R
5Be selected from C
1-6Alkyl, aryl, heteroaryl, Heterocyclylalkyl, N (R
3)
2, OR
3, halogen, N
3, CN, C
1-6Alkylidene aryl, C
1-6Alkylidene group N (R
3)
2, C (O) R
3, C (O) OR
3, C (O) N (R
3)
2, N (R
1) C (O) R
3, N (R
1) C (O) OR
3, CF
3With
R
6Be selected from OR
11,-C ≡ C-R
7And heteroaryl;
R
7Be selected from hydrogen, C
1-6Alkyl, aryl, C
1-6Alkylidene aryl, heteroaryl, C
1-6Alkylidene group heteroaryl and alkoxyl group;
R
8, R
9And R
10Independently be selected from hydrogen, halogen, the optional C that replaces
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OCF
3, CF
3, NO
2, CN, NC, N (R
3)
2, OR
3, CO
2R
3, C (O) N (R
3)
2, C (O) R
3, N (R
1) COR
3, N (R
1) C (O) OR
3, N (R
8) C (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group C (O) R
3, N (R
1) C (O) C
1-6Alkylidene group C (O) OR
3, N (R
1) C (O) C
1-3Alkylidene group OR
3, N (R
1) C (O) C
1-6Alkylidene group NHC (O) OR
3, N (R
1) C (O) C
1-6Alkylidene group SO
2NR
3, C
1-6Alkylidene group OR
3And SR
3
R
11Be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, SO
2R
4By halogen, hydroxyl, aryl, heteroaryl, N (R
4)
2And SO
2R
4In the C of one or more replacements
1-6Alkyl; C
1-6Alkylidene aryl, C
1-6Alkylidene group heteroaryl, C
1-6Alkylidene group C
3-8Heterocyclylalkyl, C
1-6Alkylidene group SO
2Aryl, the optional C that replaces
1-6Alkylidene group N (R
4)
2, OCF
3, C
1-6Alkylidene group N (R
4)
3 +, C
3-8Heterocyclylalkyl and CH (C
1-6Alkylidene group-N (R
4)
2)
2
2. the compound of claim 1, wherein
X
1And X
2For-N (H)-;
Y is O or S;
W contains at least 2 heteroatomic heteroaryls that are selected from N, O and S, and described ring is optional to be selected from C by one or two
1-6Alkyl, aryl, heteroaryl, N (R
3)
2, OR
3, C (O) N (R
3)
2, CO
2R
3, CN, CF
3Replace with the substituting group of halogen.
3. the compound of claim 2, wherein W is selected from pyridazinyl, pyrimidyl, pyrazinyl and triazinyl, and it is optional to be selected from the optional C that replaces by one or two
1-6Alkyl, aryl, heteroaryl, N (R
3)
2, OR
3, C (O) OR
3, C (O) N (R
3)
2Replace with the substituting group of halogen.
4. the compound of claim 2, wherein W is selected from
5. the compound of claim 2, wherein W is selected from
6. the compound of claim 2, wherein W is a pyrazinyl.
7. the compound of claim 1, wherein R
6Be OR
11
8. the compound of claim 1, wherein R
7Be heteroaryl.
9. the compound of claim 1, wherein heteroaryl substituting group and the R on the W
6Heteroaryl independently be selected from
10. be selected from following compound:
11. composition, it comprises on the compound of claim 1 and the medicine can accept carrier.
12. the method for check point kinases 1 in the inhibition cell, this method comprise the step that described cell is contacted with the compound of the claim 1 of significant quantity.
13. make the method for the cell sensitization of the individuality that just experiences medical conditions chemotherapy or radiotherapy, this method comprises the compound of the claim 1 of significant quantity and chemotherapeutics, radiotherapeutic agents or its mixture united and gives described individuality.
14. further comprising, the method for claim 13, this method give one or more cytokines, lymphokine, somatomedin or other Hemopoietic factors.
15. the method for claim 12, wherein said chemotherapeutics are selected from alkylating agent, metabolic antagonist, hormone or its antagonist, radio isotope, antibody and its mixture.
16. the method for claim 13, wherein said radiotherapeutic agents is selected from γ-radiation, x-ray radiation, ultraviolet ray, visible light, ir radiation and microwave radiation.
17. the method for claim 13, wherein said illness are the cancer that is selected from colorectal carcinoma, head and neck cancer, carcinoma of the pancreas, mammary cancer, cancer of the stomach, bladder cancer, carcinoma vulvae, leukemia, lymphoma, melanoma, renal cell carcinoma, ovarian cancer, brain tumor, osteosarcoma and lung cancer.
18. the method for claim 13, wherein said illness are to be selected from following cancer: mucoid circle cell carcinoma, local late tumor, metastatic carcinoma, the Ewing sarcoma, cancer metastasis, lymphatic shifts, squamous cell cancer, esophageal squamous cell carcinoma, oral carcinoma, multiple myeloma, acute lymphoblastic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, exudative lymphoma (based on the lymphoma of body cavity), thymic lymphoma lung cancer, small cell carcinoma, cutaneous T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adrenocortical carcinoma, produce the tumour of ACTH, non-small cell carcinoma, mammary cancer, small cell carcinoma, duct carcinoma, cancer of the stomach, colorectal carcinoma, colorectal carcinoma, with the relevant polyp of knot rectum tumorigenesis, carcinoma of the pancreas, liver cancer, bladder cancer, primary shallow bladder tumor, the aggressive transitional cell carcinoma of bladder, flesh aggressive bladder cancer, prostate cancer, ovarian cancer, primary peritonaeum epithelioma, cervical cancer, carcinoma of endometrium, carcinoma of vagina, carcinoma vulvae, uterus carcinoma and ovarian follicle solid tumor, carcinoma of testis, penile cancer, renal cell carcinoma, inner brain tumor, neuroblastoma, the stellate cell brain tumor, neurospongioma, attack the metastatic cancer cell of central nervous system, osteoma and osteosarcoma, malignant melanoma, the tumour progression of human skin keratinocyte, squamous cell cancer, thyroid carcinoma, the retinoblast cancer, neuroblastoma, ascites, the malignant pleural hydrops, mesothelioma, the WilmsShi tumour, carcinoma of gallbladder, trophocyte's tumour, hemangiopericytoma and Kaposi sarcoma.
19. the method for claim 12, wherein said treatment are selected from the inflammatory conditions of rheumatoid arthritis, psoriasis, vitiligo, Wegener granulomatosis and systemic lupus erythematous.
20. the method for claim 13, the compound of wherein said claim 1 are at least 20 times of protein kinase A, protein kinase C, cdc2 and pp60v-src in the selectivity aspect the inhibition Chk1.
21. the method for claim 13, the compound of wherein said claim 1 suppress selectivity aspect the Chk1 be protein kinase A, protein kinase C, cdc2 and pp60v-src 75 at least doubly.
22. the method for claim 13, the compound of wherein said claim 1 suppress selectivity aspect the Chk1 be protein kinase A, protein kinase C, cdc2, pp60v-src 100 at least doubly.
23. the method for claim 13, wherein said chemotherapeutics comprise gemcitabine, pemetrexed, cis-platinum, carboplatin, taxol or its mixture.
24. suppress the outgrowth method of abnormal cells, this method comprises with the Chk1 activator and contacting with the cell mass that comprises abnormal proliferation cell, so that the cell cycle arrest of described abnormal proliferation cell is synchronous basically, compound with claim 1 contacts with described cell mass subsequently, to cancel described cell cycle arrest basically.
25. the method for claim 24, wherein said Chk1 activator comprises at least a chemotherapeutics.
26. the method for claim 24, wherein said Chk1 activator comprises ionizing rays or uv-radiation.
27. uniting with radiation sensitizing agent, photosensitizers or its mixture, the method for claim 24, wherein said ionizing rays give.
28. the method for claim 24, wherein said abnormal proliferation cell are non-cancerous cells.
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|---|---|---|---|
| US60296804P | 2004-08-19 | 2004-08-19 | |
| US60/602,968 | 2004-08-19 |
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| Publication Number | Publication Date |
|---|---|
| CN101115727A true CN101115727A (en) | 2008-01-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800353820A Pending CN101115727A (en) | 2004-08-19 | 2005-08-18 | Compounds useful for inhibiting chk1 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20080318974A1 (en) |
| EP (1) | EP1778648A2 (en) |
| JP (1) | JP2008510719A (en) |
| KR (1) | KR20070054205A (en) |
| CN (1) | CN101115727A (en) |
| AU (1) | AU2005272586A1 (en) |
| BR (1) | BRPI0514466A (en) |
| CA (1) | CA2577880A1 (en) |
| MX (1) | MX2007002040A (en) |
| WO (1) | WO2006021002A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628659A (en) * | 2015-01-27 | 2015-05-20 | 广西师范大学 | Pyrazine-aryle urea derivatives with anti-tumor function and preparation method and application thereof |
| CN108697811A (en) * | 2016-01-11 | 2018-10-23 | 梅里麦克制药股份有限公司 | Inhibit ataxia-telangiectasia and Rad3 GAP-associated protein GAPs (ATR) |
| CN114746413A (en) * | 2019-11-29 | 2022-07-12 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201008005D0 (en) | 2010-05-13 | 2010-06-30 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| GB201119799D0 (en) | 2011-11-16 | 2011-12-28 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| GB201402277D0 (en) | 2014-02-10 | 2014-03-26 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| SI3157916T1 (en) | 2014-06-19 | 2019-05-31 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| EP3411036B1 (en) | 2016-02-04 | 2021-12-29 | Pharmaengine, Inc. | 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (chk1) inhibitors, and their preparations and applications |
| SG11201908788YA (en) | 2017-03-31 | 2019-10-30 | Seattle Genetics Inc | Combinations of chk1- and wee1 - inhibitors |
| WO2021119236A1 (en) | 2019-12-10 | 2021-06-17 | Seagen Inc. | Preparation of a chk1 inhibitor compound |
| GB202107924D0 (en) | 2021-06-03 | 2021-07-21 | Sentinel Oncology Ltd | A pharmaceutical salt |
| GB202107932D0 (en) | 2021-06-03 | 2021-07-21 | Sentinel Oncology Ltd | Preparation of a CHK1 Inhibitor Compound |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL254871A (en) * | 1959-08-14 | |||
| CH493499A (en) * | 1969-01-31 | 1970-07-15 | Agripat Sa | Antimicrobial phenylcarbamic esters |
| US4071524A (en) * | 1976-11-08 | 1978-01-31 | Riker Laboratories, Inc. | Derivatives of urea |
| DE69829412T2 (en) * | 1997-12-22 | 2005-07-28 | Bayer Pharmaceuticals Corp., West Haven | INHIBITION OF RAF KINASE USING SYMMETRIC AND UNSYMMETRIC SUBSTITUTED UREAS |
| UA76977C2 (en) * | 2001-03-02 | 2006-10-16 | Icos Corp | Aryl- and heteroaryl substituted chk1 inhibitors and their use as radiosensitizers and chemosensitizers |
| CA2484209C (en) * | 2002-05-03 | 2013-06-11 | Exelixis, Inc. | Protein kinase modulators and methods of use |
| AU2004274013A1 (en) * | 2003-09-17 | 2005-03-31 | Icos Corporation | Use of Chk1 inhibitors to control cell proliferation |
| KR20070028591A (en) * | 2004-06-25 | 2007-03-12 | 이코스 코포레이션 | Bisarylurea derivatives useful for inhibiting chk1 |
| AU2005270102A1 (en) * | 2004-07-02 | 2006-02-09 | Icos Corporation | Compounds useful for inhibiting Chk1 |
-
2005
- 2005-08-18 EP EP05810303A patent/EP1778648A2/en not_active Withdrawn
- 2005-08-18 US US11/659,389 patent/US20080318974A1/en not_active Abandoned
- 2005-08-18 AU AU2005272586A patent/AU2005272586A1/en not_active Abandoned
- 2005-08-18 KR KR1020077006216A patent/KR20070054205A/en not_active Application Discontinuation
- 2005-08-18 JP JP2007528037A patent/JP2008510719A/en active Pending
- 2005-08-18 BR BRPI0514466-3A patent/BRPI0514466A/en not_active IP Right Cessation
- 2005-08-18 WO PCT/US2005/029518 patent/WO2006021002A2/en active Application Filing
- 2005-08-18 MX MX2007002040A patent/MX2007002040A/en not_active Application Discontinuation
- 2005-08-18 CN CNA2005800353820A patent/CN101115727A/en active Pending
- 2005-08-18 CA CA002577880A patent/CA2577880A1/en not_active Abandoned
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628659A (en) * | 2015-01-27 | 2015-05-20 | 广西师范大学 | Pyrazine-aryle urea derivatives with anti-tumor function and preparation method and application thereof |
| CN108697811A (en) * | 2016-01-11 | 2018-10-23 | 梅里麦克制药股份有限公司 | Inhibit ataxia-telangiectasia and Rad3 GAP-associated protein GAPs (ATR) |
| US11787781B2 (en) | 2016-01-11 | 2023-10-17 | Celator Pharmaceuticals, Inc. | Inhibiting ataxia telangiectasia and RAD3-related protein (ATR) |
| CN114746413A (en) * | 2019-11-29 | 2022-07-12 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
| CN114746413B (en) * | 2019-11-29 | 2024-02-23 | 南京明德新药研发有限公司 | Diazaindole derivatives and application thereof as Chk1 inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2007002040A (en) | 2008-01-11 |
| WO2006021002A2 (en) | 2006-02-23 |
| WO2006021002A3 (en) | 2006-04-20 |
| EP1778648A2 (en) | 2007-05-02 |
| CA2577880A1 (en) | 2006-02-23 |
| AU2005272586A1 (en) | 2006-02-23 |
| US20080318974A1 (en) | 2008-12-25 |
| KR20070054205A (en) | 2007-05-28 |
| BRPI0514466A (en) | 2008-06-10 |
| JP2008510719A (en) | 2008-04-10 |
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Effective date of registration: 20080104 Address after: indiana Applicant after: Eli Lilly and Co. Address before: Washington State Applicant before: Icos Corp. |
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